CN101801342A - methods for producing aripiprazole suspension and freeze-dried formulation - Google Patents
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Abstract
Translated fromChineseDescription
Translated fromChinese技术领域technical field
本发明涉及一种制造阿立哌唑(aripiprazole)悬浮液的方法、以及一种制造冻干制剂的方法。The present invention relates to a method for manufacturing aripiprazole (aripiprazole) suspension, and a method for manufacturing freeze-dried preparation.
背景技术Background technique
阿立哌唑是一种公知的作为非典型的抗精神病剂的药物。对于阿立哌唑的给药，已提出使用阿立哌唑水悬浮液作为可注射制剂。具体地，通过将平均粒径为约1至约10μm的阿立哌唑悬浮在水性载体中而获得的悬浮液，已知具有优异的缓释特性和生物利用度(专利文件3)。Aripiprazole is a drug known as an atypical antipsychotic. For the administration of aripiprazole, the use of an aqueous suspension of aripiprazole has been proposed as an injectable preparation. Specifically, a suspension obtained by suspending aripiprazole having an average particle diameter of about 1 to about 10 μm in an aqueous carrier is known to have excellent sustained-release characteristics and bioavailability (Patent Document 3).
在现有技术中，在商业生产水平，将散装(bulk)阿立哌唑无菌粉碎是很困难的。例如，使用湿磨中广泛使用的陶瓷珠的球磨法具有以下问题：珠摩擦可造成污染；另外，能够在线(in-line)灭菌的球磨机目前基本上没有商业化。In the prior art, it is difficult to aseptically comminute bulk aripiprazole at a commercial production level. For example, the ball milling method using ceramic beads widely used in wet milling has the following problems: bead friction can cause contamination; in addition, ball mills capable of in-line sterilization are basically not currently commercialized.
此外，球磨粉碎法可能涉及短路(short-pass)的问题，其中一些大颗粒可能从珠子滑过。如专利文件4中所示，优选使用具有所需的小粒径的散装阿立哌唑，优选具有约100μm或更小的平均粒径，更优选约95％的晶体的粒径小于100μm且具有窄粒径分布。然而，此平均粒径为约100μm或更小的散装阿立哌唑的生产需要特殊的结晶技术，如冲击射流结晶(impinging jet crystallization)法，如专利文件4中所述。In addition, the ball milling method may involve short-pass problems, where some large particles may slip through the beads. As shown in Patent Document 4, it is preferable to use bulk aripiprazole having a desired small particle size, preferably having an average particle size of about 100 μm or less, more preferably about 95% of the crystals having a particle size of less than 100 μm and having Narrow particle size distribution. However, the production of bulk aripiprazole having an average particle diameter of about 100 μm or less requires a special crystallization technique such as impinging jet crystallization as described in Patent Document 4.
另一方面，可使用高压均质器进行粒径缩小；然而，当平均粒径为100μm以上的阿立哌唑的10％悬浮液用高压均质器粉碎时，在生产线中发生堵塞，妨碍了粉碎作用。因此，需要使用优选具有100μm或更小的平均粒径的阿立哌唑。On the other hand, particle size reduction can be performed using a high-pressure homogenizer; however, when a 10% suspension of aripiprazole having an average particle size of 100 μm or more is crushed with a high-pressure homogenizer, clogging occurs in the production line, preventing crushing effect. Therefore, it is necessary to use aripiprazole preferably having an average particle diameter of 100 μm or less.
然而，将此平均粒径为约100μm或更小的阿立哌唑悬浮在载体溶液中伴随着发泡。因此，为了制备均匀悬浮液，必须在真空下混合(参见专利文件3，实施例1和段落0089)。However, suspending the aripiprazole having an average particle diameter of about 100 μm or less in the carrier solution is accompanied by foaming. Therefore, in order to prepare a homogeneous suspension, it is necessary to mix under vacuum (see Patent Document 3, Example 1 and paragraph 0089).
当在真空下进行混合时，可能导入外界空气，需要一些措施来防止外界环境的污染。需要在此方面进行改良。When mixing is performed under vacuum, outside air may be introduced, requiring some measures to prevent contamination of the outside environment. Improvements are needed in this area.
专利文件1公开了含有水溶性差的药物的小颗粒的制备方法，包括以下步骤：Patent Document 1 discloses a method for preparing small particles containing poorly water-soluble drugs, comprising the following steps:
(a)在不含少有机溶剂的条件下，在水溶性差的药物的熔点或之上的第一温度范围内，在高剪切力下将水溶性差的药物与一种或多种表面活性物质在水性载体中混合，以形成含有药物的加热的悬浮液，其中药物是熔融的；(a) combining the poorly water soluble drug with one or more surface active substances under high shear within a first temperature range at or above the melting point of the poorly water soluble drug in the absence of minor organic solvents mixing in an aqueous carrier to form a heated suspension containing the drug in which the drug is molten;
(b)将加热的悬浮液在第一压力范围和第一温度范围内匀化以形成含有药物的加热的匀浆，其中药物是熔融的；(b) homogenizing the heated suspension within a first pressure range and a first temperature range to form a heated homogenate containing the drug, wherein the drug is molten;
(c)将加热的匀浆冷却至在水溶性差的药物的熔化温度之下的第二温度范围以形成暂时稳定的、冷却的含有药物的匀浆；(c) cooling the heated homogenate to a second temperature range below the melting temperature of the poorly water soluble drug to form a transiently stable, cooled drug-containing homogenate;
(d)在药物的熔点之下的第二温度范围和第二压力范围内，对冷却的匀浆施加颗粒稳定高能工艺，以形成含有药物的稳定小颗粒的冷却分散液；以及(d) subjecting the cooled homogenate to a particle stabilization high energy process in a second temperature range below the melting point of the drug and in a second pressure range to form a cooled dispersion of stable small particles containing the drug; and
(e)将冷却分散液干燥以形成含有水溶性差的药物的干燥小颗粒。(e) The cooled dispersion is dried to form dry small particles containing the poorly water soluble drug.
然而，在专利文件1的方法中，在比药物的熔点高的温度下加热制备乳液是必要的，并且在保持晶型方面存在问题。However, in the method of Patent Document 1, heating at a temperature higher than the melting point of the drug is necessary to prepare the emulsion, and there is a problem in maintaining the crystal form.
专利文件2公开了一种通过加入预定量的油性成分(脂肪)、乳化剂和环糊精的组合对水溶性差的化合物有效增溶或分散的手段。其教导了使用高速搅拌机(homomixer)用于粗乳化，以及使用高压均质器或超声均质器用于细乳化。然而，在专利文件2中，被增溶或分散的含有水溶性差的化合物的组合物采取了脂肪乳液的形式，而不是水性悬浮液。Patent Document 2 discloses a means of efficiently solubilizing or dispersing poorly water-soluble compounds by adding a combination of a predetermined amount of an oily component (fat), an emulsifier, and a cyclodextrin. It teaches the use of a homomixer for coarse emulsification, and the use of a high-pressure homogenizer or an ultrasonic homogenizer for fine emulsification. However, in Patent Document 2, the solubilized or dispersed composition containing the poorly water-soluble compound takes the form of a fatty emulsion instead of an aqueous suspension.
专利文件3公开了一种用于制备无菌冻干制剂的方法，包括以下步骤：Patent document 3 discloses a method for preparing a sterile freeze-dried preparation, comprising the following steps:
(a)制备具有所需粒径分布的无菌散装阿立哌唑；(a) preparing sterile bulk aripiprazole having the desired particle size distribution;
(b)制备用于无菌散装阿立哌唑的无菌载体；(b) preparing a sterile carrier for sterile bulk aripiprazole;
(c)将无菌阿立哌唑与无菌载体混合以形成包括无菌固体混合物的无菌初级悬浮液；(c) mixing sterile aripiprazole with a sterile carrier to form a sterile primary suspension comprising a mixture of sterile solids;
(d)通过例如无菌湿磨法将无菌初级悬浮液中的无菌固体混合物的平均粒径减小至约1至约100μm的范围，尤其是约1至10的μm的范围，以形成无菌的最终悬浮液；以及(d) reducing the mean particle size of the sterile solid mixture in the sterile primary suspension to a range of about 1 to about 100 μm, especially about 1 to 10 μm, for example by aseptic wet milling, to form sterile final suspension; and
(e)将无菌的最终悬浮液冻干以形成冻干制剂。(e) The sterile final suspension is lyophilized to form a lyophilized formulation.
其教导了湿球磨法优选作为步骤(d)中的无菌湿磨工序。It teaches that wet ball milling is preferred as the aseptic wet milling procedure in step (d).
非专利文件1公开了微射流均质机(microfluidizer)与减少平均粒径的其它方法相比具有两个优点：最终产品没有污染，且生成易于大规模化。Non-Patent Document 1 discloses that a microfluidizer has two advantages over other methods of reducing the average particle size: no contamination of the final product, and easy large-scale production.
专利文件1：日本未审查的专利公开第2003-531162号Patent Document 1: Japanese Unexamined Patent Publication No. 2003-531162
专利文件2：日本未审查的专利公开第2005-22989号Patent Document 2: Japanese Unexamined Patent Publication No. 2005-22989
专利文件3：日本未审查的专利公开第2007-509148号Patent Document 3: Japanese Unexamined Patent Publication No. 2007-509148
专利文件4：日本未审查的专利公开第2007-509153号Patent Document 4: Japanese Unexamined Patent Publication No. 2007-509153
专利文件5：日本专利第3760264号Patent Document 5: Japanese Patent No. 3760264
专利文件6：日本专利第3750023号Patent Document 6: Japanese Patent No. 3750023
非专利文件1：Kathleen J.Illing等人，“Use of MicrofluidizerProcessing for Preparation of Pharmaceutical Suspensions(使用微射流均质机处理制备药物悬浮液)”，Pharm.Tech.，1996年10月，第78-88页。Non-Patent Document 1: Kathleen J.Illing et al., "Use of Microfluidizer Processing for Preparation of Pharmaceutical Suspensions (Using Microfluidizer Homogenizer to Prepare Pharmaceutical Suspensions)", Pharm.Tech., October 1996, No. 78-88 Page.
非专利文件2：“Study on Crystal Transformation ofAripiprazole(阿立哌唑的结晶变换的研究)”，Satoshi Aoki等人，The Fourth Japan-KoreaSymposium on Separation Technology(1996年10月6日至8日)，第937-940页。Non-Patent Document 2: "Study on Crystal Transformation of Aripiprazole (Research on Crystal Transformation of Aripiprazole)", Satoshi Aoki et al., The Fourth Japan-Korea Symposium on Separation Technology (October 6-8, 1996), p. Pages 937-940.
发明内容Contents of the invention
本发明要解决的问题The problem to be solved by the present invention
通过将平均粒径约1至约10μm的阿立哌唑悬浮在水性载体中而制备的悬浮液，已知具有优异的缓释特性。湿球研磨优选具有约100μm或更小的平均粒径、更优选约95％的晶体具有100μm或更小的粒径的阿立哌唑，已知是用于制造平均粒径1至10μm的阿立哌唑悬浮液的工艺，如专利文件3和4所示。A suspension prepared by suspending aripiprazole having an average particle diameter of about 1 to about 10 μm in an aqueous carrier is known to have excellent sustained-release characteristics. Wet ball milling preferably has an average particle size of about 100 μm or less, more preferably about 95% of the crystals have a particle size of 100 μm or less, and is known to be used to manufacture aripiprazole with an average particle size of 1 to 10 μm. The technology of the lipiprazole suspension is shown in patent documents 3 and 4.
然而，平均粒径约100μm或更小的散装阿立哌唑的制造需要特殊方法，诸如用于制备大体积制剂的冲击射流结晶法。在将平均粒径约100μm或更小的散装阿立哌唑悬浮在载体中的步骤中，必须在真空下混合。However, the manufacture of bulk aripiprazole with an average particle size of about 100 μm or less requires special methods such as impingement jet crystallization for the preparation of bulky formulations. In the step of suspending bulk aripiprazole having an average particle diameter of about 100 [mu]m or less in the carrier, it is necessary to mix under vacuum.
为此原因，需要生产方法可使用通过分批结晶产生的散装粉末而不需要真空混合，其含有10％或更多量的粒径为100μm或更大的阿立哌唑颗粒，优选平均粒径100μm以上、特别是约110μm至1000μm、更优选200μm至400μm的散装粉末。For this reason, there is a need for a production method that can use bulk powder produced by batch crystallization without vacuum mixing, which contains 10% or more of aripiprazole particles having a particle diameter of 100 μm or more, preferably an average particle diameter Bulk powder of 100 μm or more, especially about 110 μm to 1000 μm, more preferably 200 μm to 400 μm.
此外，湿球磨法具有以下缺点：珠摩擦可能会造成污染，且能够在线灭菌的球磨机目前没有商业化。因此，需要几乎不会引起污染并使用能够在线灭菌的生产装置的方法。In addition, the wet ball milling method has the disadvantages that bead friction may cause contamination, and ball mills capable of in-situ sterilization are not currently commercially available. Therefore, there is a need for a method that causes little contamination and uses a production device that can be sterilized in place.
解决问题的手段means of solving problems
本发明人发现，即使当使用如下的散装阿立哌唑时，该散装阿立哌唑含有10％或更多的粒径为100μm或更大的阿立哌唑颗粒并具有20μm至1000μm的平均粒径，优选具有100μm以上、特别优选110μm至1000μm、最优选200μm至400μm的平均粒径，上述问题可通过以下方式解决：使用诸如高剪切高速搅拌机的高剪切粉碎机、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、或诸如高压均质器的高压喷射式乳化分散机进行第一粉碎步骤；并使用诸如高压均质器的高压喷射式乳化分散机进一步进行第二粉碎步骤。The present inventors have found that even when bulk aripiprazole containing 10% or more of aripiprazole particles having a particle diameter of 100 μm or more and having an average particle size of 20 μm to 1000 μm is used The particle size preferably has an average particle size of 100 μm or more, particularly preferably 110 μm to 1000 μm, most preferably 200 μm to 400 μm, and the above-mentioned problems can be solved by using a high-shear pulverizer such as a high-shear high-speed mixer, applying a shear force A disperser applied to the material to be processed, a colloid mill, an ultrasonic disperser, or a high-pressure jet emulsification disperser such as a high-pressure homogenizer for the first crushing step; and using a high-pressure jet emulsification dispersion such as a high-pressure homogenizer The machine further carries out the second crushing step.
基于这些发现和进一步的研究完成了本发明，并提供下列的制造方法：The present invention has been accomplished based on these findings and further studies, and provides the following manufacturing methods:
第1项：一种制造阿立哌唑悬浮液的方法，包括以下步骤：Item 1: A method for manufacturing an aripiprazole suspension comprising the steps of:
(a)将散装阿立哌唑与载体混合以形成初级悬浮液；(a) mixing bulk aripiprazole with a carrier to form a primary suspension;
(b)使初级悬浮液经受第一次粉碎以形成二级悬浮液；以及(b) subjecting the primary suspension to a first comminution to form a secondary suspension; and
(c)使二级悬浮液经受第二次粉碎以形成最终悬浮液。(c) Subjecting the secondary suspension to a second comminution to form the final suspension.
第2项：根据第1项所述的方法，其中在步骤(b)的第一次粉碎中，通过使用高剪切粉碎机、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、或高压喷射式乳化分散机，将初级悬浮液粉碎以形成二级悬浮液，并且在步骤(c)的第二次粉碎中，通过使用高压喷射式乳化分散机将二级悬浮液粉碎以形成最终悬浮液。Item 2: The method according to item 1, wherein in the first pulverization of step (b), by using a high-shear pulverizer, a disperser that applies a shear force to the material to be processed, a colloid mill machine, ultrasonic disperser, or high-pressure jet emulsification disperser, the primary suspension is crushed to form a secondary suspension, and in the second pulverization of step (c), the secondary suspension is pulverized by using a high-pressure jet emulsification disperser The suspension is comminuted to form the final suspension.
第3项：根据第1或2项所述的方法，其中在步骤(b)的第一次粉碎中，通过使用高剪切粉碎机或将剪切力施加于待加工的材料的分散机将初级悬浮液粉碎以形成二级悬浮液，并且在步骤(c)的第二次粉碎中，通过使用高压均质器将二级悬浮液粉碎以形成最终悬浮液。Item 3: The method according to Item 1 or 2, wherein in the first pulverization of step (b), the The primary suspension is comminuted to form a secondary suspension, and in the second comminution of step (c), the secondary suspension is comminuted to form a final suspension by using a high pressure homogenizer.
第4项：根据第3项所述的方法，其中在步骤(c)中，高压均质器在300至1000bar的粉碎压力下使用。Item 4: The method according to item 3, wherein in step (c), a high pressure homogenizer is used at a crushing pressure of 300 to 1000 bar.
第5项：根据第3或4项所述的方法，其中在步骤(c)中，高压均质器在300至600bar的粉碎压力下使用。Item 5: The method according to item 3 or 4, wherein in step (c), a high pressure homogenizer is used at a crushing pressure of 300 to 600 bar.
第6项：根据第3至5项中任何一项所述的方法，其中在步骤(c)中，高压均质器在1至70℃的入口温度下使用。Item 6: The method according to any one of Items 3 to 5, wherein in step (c), the high pressure homogenizer is used at an inlet temperature of 1 to 70°C.
第7项：根据第1或2项所述的方法，其中在步骤(b)的第一次粉碎中，通过使用高压均质器将初级悬浮液粉碎以形成二级悬浮液，并且在步骤(c)的第二次粉碎中，通过使用高压均质器将二级悬浮液粉碎以形成最终悬浮液。Item 7: The method according to Item 1 or 2, wherein in the first pulverization of step (b), the primary suspension is pulverized by using a high-pressure homogenizer to form a secondary suspension, and in step ( In the second pulverization of c), the secondary suspension is pulverized by using a high pressure homogenizer to form a final suspension.
第8项：根据第1、2或7项所述的方法，其中在步骤(b)的第一次粉碎中，通过使用高压均质器在50至200bar的粉碎压力下将初级悬浮液粉碎以形成二级悬浮液，并且在步骤(c)的第二次粉碎中，通过使用高压均质器在200至1000bar的粉碎压力下将二级悬浮液粉碎以形成最终悬浮液，其中步骤(b)中的粉碎压力与步骤(c)中的粉碎压力之间的差为100至900bar。Item 8: The method according to item 1, 2 or 7, wherein in the first pulverization of step (b), the primary suspension is pulverized by using a high-pressure homogenizer at a pulverization pressure of 50 to 200 bar to A secondary suspension is formed, and in the second pulverization of step (c), the secondary suspension is pulverized under a pulverization pressure of 200 to 1000 bar by using a high-pressure homogenizer to form a final suspension, wherein step (b) The difference between the crushing pressure in step (c) and the crushing pressure in step (c) is 100 to 900 bar.
第9项：根据第8项所述的方法，其中在步骤(b)中，高压均质器的粉碎压力在50至200bar的范围内，并且在步骤(c)中，粉碎被进行多次，且粉碎压力在200至1000bar的范围内逐步提高。Item 9: The method according to item 8, wherein in step (b), the crushing pressure of the high pressure homogenizer is in the range of 50 to 200 bar, and in step (c), the crushing is performed multiple times, And the crushing pressure is gradually increased in the range of 200 to 1000 bar.
第10项：根据第9项所述的方法，其中在步骤(c)中，高压均质器的最终粉碎压力为300至600bar。Item 10: The method according to Item 9, wherein in step (c), the final crushing pressure of the high pressure homogenizer is 300 to 600 bar.
第11项：根据第7至10项中任何一项所述的方法，其中在步骤(b)和(c)中，高压均质器在1至50℃的入口温度下使用。Item 11: The method according to any one of items 7 to 10, wherein in steps (b) and (c), the high pressure homogenizer is used at an inlet temperature of 1 to 50°C.
第12项：根据第1至11项中任何一项所述的方法，其中载体含有选自羟甲基纤维素、羟甲基纤维素盐类、羟丙基纤维素、羟丙基乙基纤维素、羟丙基甲基纤维素和聚乙烯基吡咯烷酮的至少一种悬浮剂。Item 12: The method according to any one of items 1 to 11, wherein the carrier contains hydroxymethyl cellulose, hydroxymethyl cellulose salts, hydroxypropyl cellulose, hydroxypropyl ethyl cellulose At least one suspending agent of ketone, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
第13项：根据第1至12项中任何一项所述的方法，其中散装阿立哌唑含有10％或更多的具有100μm或更大的粒径的阿立哌唑颗粒，且其具有20μm至1000μm的平均粒径。Item 13: The method according to any one of items 1 to 12, wherein the bulk aripiprazole contains 10% or more of aripiprazole particles having a particle diameter of 100 μm or more, and which has Average particle size from 20 μm to 1000 μm.
第14项：根据第1至13项中任何一项所述的方法，其中散装阿立哌唑具有大于100μm的平均粒径。Item 14: The method according to any one of items 1 to 13, wherein the bulk aripiprazole has an average particle size greater than 100 μm.
第15项：根据第1至14项中任何一项所述的方法，其中散装阿立哌唑具有110μm至1000μm的平均粒径。Item 15: The method according to any one of items 1 to 14, wherein the bulk aripiprazole has an average particle diameter of 110 μm to 1000 μm.
第16项：根据第1至15项中任何一项所述的方法，其中散装阿立哌唑具有200μm至400μm的平均粒径。Item 16: The method according to any one of items 1 to 15, wherein the bulk aripiprazole has an average particle diameter of 200 μm to 400 μm.
第17项：根据第1至16项中任何一项所述的方法，其中阿立哌唑悬浮液中的阿立哌唑具有1至10μm的平均粒径。Item 17: The method according to any one of Items 1 to 16, wherein the aripiprazole in the aripiprazole suspension has an average particle diameter of 1 to 10 μm.
第18项：根据第1至17项中任何一项所述的方法，其中阿立哌唑悬浮液中的阿立哌唑具有1至5μm的平均粒径。Item 18: The method according to any one of Items 1 to 17, wherein the aripiprazole in the aripiprazole suspension has an average particle diameter of 1 to 5 μm.
第19项：根据第1至18项中任何一项所述的方法，其中阿立哌唑悬浮液中的阿立哌唑具有2至4μm的平均粒径。Item 19: The method according to any one of Items 1 to 18, wherein the aripiprazole in the aripiprazole suspension has an average particle diameter of 2 to 4 μm.
第20项：根据第1至19项中任何一项所述的方法，其中阿立哌唑悬浮液中的阿立哌唑具有2至3μm的平均粒径。Item 20: The method according to any one of Items 1 to 19, wherein the aripiprazole in the aripiprazole suspension has an average particle diameter of 2 to 3 μm.
第21项：根据第1至6项中任何一项所述的方法，包括以下步骤：Item 21: The method according to any one of items 1 to 6, comprising the steps of:
(I)将具有200μm至400μm的平均粒径的无菌散装阿立哌唑与无菌载体(优选含有羟甲基纤维素钠盐的无菌载体)混合以形成无菌初级悬浮液；(I) mixing sterile bulk aripiprazole having an average particle size of 200 μm to 400 μm with a sterile carrier, preferably one containing hydroxymethylcellulose sodium salt, to form a sterile primary suspension;
(II)使用高剪切粉碎机或将剪切力施加于待加工的材料的分散机使无菌初级悬浮液经受第一次粉碎，以形成无菌二级悬浮液；以及(II) subjecting the sterile primary suspension to a first comminution using a high shear pulverizer or a disperser that applies shear forces to the material to be processed to form a sterile secondary suspension; and
(III)使用高压均质器使无菌二级悬浮液经受第二次粉碎，以形成无菌最终悬浮液；(III) subjecting the sterile secondary suspension to a second comminution using a high pressure homogenizer to form a sterile final suspension;
其中无菌最终悬浮液(即，所需的无菌阿立哌唑悬浮液)中的阿立哌唑具有1至10μm(优选1至5μm，特别是2至4μm)的平均粒径。Wherein the aripiprazole in the sterile final suspension (ie the desired sterile aripiprazole suspension) has an average particle size of 1 to 10 μm, preferably 1 to 5 μm, especially 2 to 4 μm.
第22项：根据第1至21项中任何一项所述的方法，其中散装阿立哌唑为选自一水合物和酐晶体B(Anhydride Crystals B)的形式。Item 22: The method according to any one of items 1 to 21, wherein the bulk aripiprazole is in a form selected from monohydrate and anhydride crystals B (Anhydride Crystals B).
第23项：根据第1至22项中任何一项所述的方法，进一步包括用具有10至225μm的公称过滤精度(nominal filtration rating)的滤器过滤最终悬浮液的步骤。Item 23: The method according to any one of items 1 to 22, further comprising the step of filtering the final suspension with a filter having a nominal filtration rating of 10 to 225 μm.
第24项：一种制造阿立哌唑水合物A的冻干制剂的方法，该方法包括以下步骤：将根据第1至23项中任何一项所述的方法制造并含有阿立哌唑水合物A的悬浮液冷却至-20至-55℃以冷冻该悬浮液；并且随后在约0℃以下进行干燥。Item 24: A method of manufacturing a lyophilized preparation of aripiprazole hydrate A, the method comprising the steps of: preparing and containing aripiprazole hydrate according to the method described in any one of items 1 to 23. The suspension of Substance A is cooled to -20 to -55°C to freeze the suspension; and then dried below about 0°C.
第25项：一种制造含有无水形式的阿立哌唑的冻干制剂的方法，该方法包括以下三步骤：Item 25: A method of manufacturing a lyophilized formulation containing aripiprazole in anhydrous form, the method comprising the following three steps:
(1)将阿立哌唑悬浮液冷却至-20至-55℃以冷冻该悬浮液，所述阿立哌唑悬浮液是使用一水合物或无水晶体形式的散装阿立哌唑，通过根据第1至23项中任何一项所述的方法制造的；(1) Cooling the aripiprazole suspension, which is bulk aripiprazole in the form of monohydrate or anhydrous crystals, to -20 to -55°C to freeze the suspension, by Manufactured by the method mentioned in any one of items 1 to 23;
(2)在低于约0℃的温度进行初步干燥；以及(2) performing preliminary drying at a temperature below about 0°C; and
(3)在高于约0℃的温度进行第二次干燥。(3) The second drying is carried out at a temperature higher than about 0°C.
本发明的效果Effect of the present invention
本发明提供了如下所述的优异效果。The present invention provides excellent effects as described below.
(a)当使用如下的散装阿立哌唑时，根据本发明的制造阿立哌唑悬浮液的方法特别有效，该方法包括散装阿立哌唑的两步粉碎，该散装阿立哌唑含有至少10％的粒径为100μm或更大的阿立哌唑颗粒并具有20μm至1000μm的平均粒径，优选具有100μm以上、特别是110μm至1000μm、最优选200μm至400μm的平均粒径的散装阿立哌唑。然而，不论平均粒径大小如何，本发明的方法都能很容易地生产平均粒径为1至10μm、优选1至5μm、更优选2至4μm、最优选2至3μm的阿立哌唑悬浮液。(a) The method of manufacturing an aripiprazole suspension according to the present invention is particularly effective when using bulk aripiprazole comprising a two-step pulverization of bulk aripiprazole containing At least 10% of aripiprazole particles having a particle size of 100 μm or more and having an average particle size of 20 μm to 1000 μm, preferably bulk aripiprazole having an average particle size of 100 μm or more, especially 110 μm to 1000 μm, most preferably 200 μm to 400 μm Ripiprazole. However, regardless of the average particle size, the process of the present invention can easily produce an aripiprazole suspension having an average particle size of 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably 2 to 3 μm .
(b)根据本发明，通过进行两步粉碎，即，使用高剪切粉碎机(例如高剪切高速搅拌机)、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、或高压喷射式分散机(例如高压均质器)的第一次粉碎步骤，以及使用高压喷射式分散机(例如高压均质器)的第二次粉碎步骤，可制备平均粒径为1至10μm的阿立哌唑悬浮液，甚至使用通过分批结晶等获得的具有较大平均粒径的大体积粉末，尤其是平均粒径100μm以上的散装阿立哌唑。因此，不象专利文件4，对于散装阿立哌唑的制备不需要类似冲击射流结晶法的特殊结晶技术。(b) According to the present invention, by performing pulverization in two steps, namely, using a high-shear pulverizer (such as a high-shear high-speed mixer), a disperser that applies a shear force to the material to be processed, a colloid mill, ultrasonic dispersion machine, or the first pulverization step of a high-pressure jet disperser (such as a high-pressure homogenizer), and the second pulverization step using a high-pressure jet disperser (such as a high-pressure homogenizer), the average particle size of 1 Aripiprazole suspensions up to 10 μm, even bulky powders obtained by batch crystallization etc. with a larger average particle size, especially bulk aripiprazole with an average particle size of 100 μm or more are used. Therefore, unlike Patent Document 4, no special crystallization technique like impingement jet crystallization is required for the preparation of bulk aripiprazole.
(c)本发明的方法使用含有至少10％的粒径为100μm或更大的阿立哌唑颗粒并具有20μm至1000μm的平均粒径的散装阿立哌唑，优选具有100μm以上、特别是110μm至1000μm、最优选200μm至400μm的平均粒径的散装阿立哌唑作为无菌散装阿立哌唑，因此可不采用如专利文件3中使用的真空混合工艺来进行散装阿立哌唑与载体的混合步骤、第一次粉碎步骤和第二次粉碎步骤。这消除了在无菌制剂的生产期间外界空气与制剂混合的可能性，为生产无菌产品的方法提供了极大的优势。(c) The method of the present invention uses bulk aripiprazole containing at least 10% of aripiprazole particles having a particle size of 100 μm or more and having an average particle size of 20 μm to 1000 μm, preferably 100 μm or more, especially 110 μm Bulk aripiprazole with an average particle diameter of 1000 μm, most preferably 200 μm to 400 μm is used as sterile bulk aripiprazole, so the vacuum mixing process of bulk aripiprazole and carrier can be carried out without adopting the vacuum mixing process as used in Patent Document 3. Mixing step, first pulverization step and second pulverization step. This eliminates the possibility of ambient air mixing with the formulation during production of the sterile formulation, providing a great advantage to the process of producing sterile products.
(d)此外，由于在球磨机中不发生研磨，因此没有该研磨所引起的污染问题。(d) Furthermore, since grinding does not take place in the ball mill, there is no contamination problem caused by the grinding.
(e)不太可能发生大颗粒的短路，其是湿球磨中发生的问题，因此获得没有阿立哌唑粗颗粒的均匀悬浮液。结果，阿立哌唑悬浮液可用较小的孔径过滤以在粉碎后去除外来物质，并且从控制外来物质的观点来看是有益的。(e) Short circuiting of large particles is less likely to occur, which is a problem that occurs in wet ball milling, thus obtaining a homogeneous suspension free of coarse aripiprazole particles. As a result, the aripiprazole suspension can be filtered with a smaller pore size to remove foreign substances after pulverization, and it is beneficial from the viewpoint of controlling foreign substances.
(f)在商业规模的无菌生产中，就诸如球磨机的装置而言，难以进行原位清洗(CIP)和原位灭菌(SIP)；然而，在本发明的粉碎法(第一次粉碎步骤和第二次粉碎步骤)中使用的生产装置允许进行CIP和SIP。因此，通过在线灭菌很容易使装置保持无菌。(f) In aseptic production on a commercial scale, cleaning in place (CIP) and sterilization in place (SIP) are difficult for devices such as ball mills; step and the second pulverization step) the production equipment used allows to carry out CIP and SIP. Therefore, it is easy to keep the device sterile by sterilization in place.
(g)当为本制造方法中的载体选择羧甲基纤维素或其盐作为悬浮剂时，能够避免过度粉碎而使平均粒径低于1μm以下。(g) When carboxymethyl cellulose or its salt is selected as the suspending agent as the carrier in this production method, excessive pulverization can be avoided and the average particle diameter can be kept below 1 μm.
具体实施方式Detailed ways
本发明的制造方法在下面进行详述。The production method of the present invention is described in detail below.
在本发明中，术语“平均粒径”是指通过激光光散射(LLS)法测定的体积平均直径。粒径分布通过LLS法测定，且平均粒径由粒径分布进行计算。In the present invention, the term "average particle diameter" refers to a volume average diameter measured by a laser light scattering (LLS) method. The particle size distribution is measured by the LLS method, and the average particle size is calculated from the particle size distribution.
散装阿立哌唑Bulk Aripiprazole
阿立哌唑具有如下结构Aripiprazole has the structure
[式1][Formula 1]
并且是用于治疗精神分裂症的非典型抗精神病剂。其水溶性差(室温下＜1μg/ml)。and is an atypical antipsychotic used in the treatment of schizophrenia. It has poor water solubility (<1 μg/ml at room temperature).
阿立哌唑散装药物或大体积粉末可具有任意的平均粒径和粒径分布。通常，优选使用含有至少10％比例的粒径为100μm或更大的阿立哌唑颗粒，并具有20μm至1000μm的平均粒径的散装阿立哌唑，优选平均粒径为100μm以上、特别是110μm至1000μm、最优选200μm至400μm的散装阿立哌唑。Aripiprazole bulk drug product or bulk powder can have any average particle size and particle size distribution. In general, it is preferred to use bulk aripiprazole containing at least a 10% proportion of aripiprazole particles having a particle size of 100 μm or larger and having an average particle size of 20 μm to 1000 μm, preferably an average particle size of 100 μm or more, especially Aripiprazole in bulk from 110 μm to 1000 μm, most preferably from 200 μm to 400 μm.
此外，散装阿立哌唑的晶型不受限制，并且可使用各种晶型。阿立哌唑的晶型的实例包括在非专利文件2中公开的一水合物(在本说明书中，此术语“一水合物”是指非专利文件2中公开的一水合物)、在专利文件5中公开的水合物A和酐晶体B、在专利文件6中公开的酐晶体C、酐晶体D、酐晶体E、酐晶体F和酐晶体G。其中，优选一水合物和酐晶体B。In addition, the crystal form of bulk aripiprazole is not limited, and various crystal forms can be used. Examples of crystal forms of aripiprazole include the monohydrate disclosed in Non-Patent Document 2 (in this specification, the term "monohydrate" refers to the monohydrate disclosed in Non-Patent Document 2), Hydrate A and anhydride crystal B disclosed in Document 5, anhydride crystal C, anhydride crystal D, anhydride crystal E, anhydride crystal F, and anhydride crystal G disclosed in Patent Document 6. Among them, monohydrate and anhydride crystals B are preferred.
在本发明中，通过使用一水合物晶体(非专利文件2)作为散装阿立哌唑，通过本发明的方法获得水合物A(专利文件5)的悬浮液。通过使用水合物A作为散装阿立哌唑，也可通过本发明的方法获得水合物A的悬浮液。酐晶体B(专利文件5)、酐晶体C、酐晶体D、酐晶体E、酐晶体F和酐晶体G(专利文件6)也可用作散装阿立哌唑。使用这些晶体，获得其中混合有水合物A和无水阿立哌唑的阿立哌唑悬浮液。另外，酐晶体B、酐晶体C、酐晶体D、酐晶体E、酐晶体F或酐晶体G可预先从乙醇和水等中重结晶，从而制备一水合物，并且得到的一水合物可用作散装阿立哌唑。In the present invention, by using monohydrate crystals (Non-Patent Document 2) as bulk aripiprazole, a suspension of Hydrate A (Patent Document 5) is obtained by the method of the present invention. By using Hydrate A as bulk aripiprazole, a suspension of Hydrate A can also be obtained by the process of the present invention. Anhydride crystals B (patent document 5), anhydride crystals C, anhydride crystals D, anhydride crystals E, anhydride crystals F and anhydride crystals G (patent document 6) can also be used as bulk aripiprazole. Using these crystals, an aripiprazole suspension in which Hydrate A and anhydrous aripiprazole were mixed was obtained. In addition, anhydride crystals B, anhydride crystals C, anhydride crystals D, anhydride crystals E, anhydride crystals F, or anhydride crystals G can be recrystallized from ethanol and water etc. in advance to prepare a monohydrate, and the obtained monohydrate can be used For bulk aripiprazole.
载体carrier
本发明中使用的载体包括：Carriers used in the present invention include:
(1)一种或多种悬浮剂，(1) one or more suspending agents,
(2)注射用水，(2) water for injection,
(3)任选地一种或多种填充剂或等渗剂，(3) optionally one or more fillers or isotonic agents,
(4)任选地一种或多种缓冲液，以及(4) optionally one or more buffers, and
(5)任选地一种或多种pH调节剂。(5) Optionally one or more pH adjusters.
基于无菌可注射制剂(本发明的阿立哌唑悬浮液)的总重量，悬浮剂的存在量可以在约0.2至约10wt％的范围内，优选约0.3至约5wt％，更优选约0.4至约0.9wt％。适合使用的悬浮剂的实例包括但不限于，下列的一种、两种或多种：羧甲基纤维素或其盐(例如，羧甲基纤维素钠)、羟丙基纤维素、羟丙基乙基纤维素、羟丙基甲基纤维素、和聚乙烯基吡咯烷酮，优选羧甲基纤维素或其盐，特别是钠盐。其他适合在用于阿立哌唑的载体中使用的悬浮剂包括各种聚合物、低分子量低聚物、天然产品、和表面活性剂，包括非离子型和离子型表面活性剂，如氯化十六烷基吡啶、明胶、酪蛋白、卵磷脂(磷脂类)、葡聚糖、甘油、阿拉伯树胶、胆固醇、黄蓍胶、硬脂酸、苯扎氯铵、硬脂酸钙、单硬脂酸甘油酯、十六十八醇、聚西托醇乳化蜡、脱水山梨醇酯、聚氧乙烯烷基醚(例如，诸如聚西托醇1000的聚乙二醇醚)、聚氧乙烯蓖麻油衍生物、聚氧乙烯脱水山梨醇脂肪酸酯(例如，市售的Tweens(注册商标)；例如Tween 20(注册商标)和Tween 80(注册商标)(ICI Specialty Chemicals))；聚乙二醇(例如，Carbowaxs3350(注册商标)和1450(注册商标)、和Carbopol 934(注册商标)(Union Carbide))、十二烷基三甲基溴化铵、聚氧乙烯硬脂酸酯、胶体二氧化硅、磷酸盐、十二烷基硫酸钠、羧甲基纤维素钙、羟丙基纤维素(例如，HPC、HPC-SL和HPC-L)、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、非结晶纤维素、硅酸铝镁盐、三乙醇胺、聚乙烯醇(PVA)、具有环氧乙烷和甲醛的4-(1，1，3，3-四甲基丁基)-苯酚聚合物(也称为四丁酚醛、superione和triton)、泊洛沙姆(例如，Pluronics F68(注册商标)和F108(注册商标)，其是环氧乙烷和环氧丙烷的嵌段共聚物)；poloxamines(例如，Tetronic 908(注册商标)，也称为Poloxamine 908(注册商标)，其是由环氧丙烷和环氧乙烷顺序地加成至乙二胺上得到的四官能化嵌段共聚物(BASF Wyandotte Corporation，Parsippany，N.J.))；带电荷的磷脂，诸如二肉豆蔻酰磷脂酰甘油、磺基琥珀酸二辛酯(DOSS)；Tetronic 1508(注册商标)(T-1508)(BASF WyandotteCorporation)、磺基琥珀酸钠的二烷基酯(例如，Aerosol OT(注册商标)，其是磺基琥珀酸钠的二辛基酯(American Cyanamid))；Duponol P(注册商标)，其是十二烷基硫酸钠(DuPont)；Tritons X-200(注册商标)，其是烷基芳基聚醚磺酸酯(Rohm and Haas)；Crodestas F-110(注册商标)，其是蔗糖硬脂酸酯与蔗糖二硬脂酸酯的混合物(Croda Inc.)；对异壬基苯氧基聚-(缩水甘油)，也称为Olin-10G(注册商标)或Surfactant 10-G(注册商标)(Olin Chemicals，Stamford，Conn.)；CrodestasSL-40(注册商标)(Croda，Inc.)；和SA9OHCO，其是C18H37CH2(CON(CH3))-CH2(CHOH)4(CH2OH)2(Eastman Kodak Co.)；癸酰基-N-甲基葡糖酰胺；n-癸基-β-D-吡喃葡萄糖苷；n-癸基-β-D-吡喃麦芽糖苷；n-十二烷基-β-D-吡喃葡萄糖苷；n-十二烷基-β-D-麦芽苷；庚酰基-N-甲基葡糖酰胺；n-庚基-β-D-吡喃葡萄糖苷；n-庚基-β-D-硫葡糖苷；n-己基-β-D-吡喃葡萄糖苷；壬酰基-N-甲基葡糖酰胺；n-壬基-β-D-吡喃葡萄糖苷；辛酰基-N-甲基葡糖酰胺；n-辛基-β-D-吡喃葡萄糖苷；辛基-β-D-硫代吡喃葡萄糖苷；和类似物。Based on the total weight of the sterile injectable preparation (aripiprazole suspension of the present invention), the suspending agent may be present in an amount ranging from about 0.2 to about 10 wt%, preferably from about 0.3 to about 5 wt%, more preferably about 0.4 to about 0.9 wt%. Examples of suitable suspending agents include, but are not limited to, one, two or more of the following: carboxymethylcellulose or a salt thereof (e.g., sodium carboxymethylcellulose), hydroxypropylcellulose, hydroxypropyl ethylethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone, preferably carboxymethylcellulose or a salt thereof, especially the sodium salt. Other suspending agents suitable for use in vehicles for aripiprazole include various polymers, low molecular weight oligomers, natural products, and surfactants, including nonionic and ionic surfactants, such as chlorinated Cetylpyridine, Gelatin, Casein, Lecithin (Phospholipids), Dextran, Glycerin, Gum Arabic, Cholesterol, Tragacanth, Stearic Acid, Benzalkonium Chloride, Calcium Stearate, Monostearate Glyceryl Acids, Cetostearyl Alcohol, Pecetor Emulsifying Wax, Sorbitan Ester, Polyoxyethylene Alkyl Ethers (e.g., Polyethylene Glycol Ethers such as Ceitol 1000), Polyoxyethylene Castor Oil Derivatives, polyoxyethylene sorbitan fatty acid esters (for example, commercially available Tweens (registered trademark); such as Tween 20 (registered trademark) and Tween 80 (registered trademark) (ICI Specialty Chemicals)); polyethylene glycol ( For example, Carbowaxs 3350 (registered trademark) and 1450 (registered trademark), and Carbopol 934 (registered trademark) (Union Carbide)), lauryltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide , phosphate, sodium lauryl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose (eg, HPC, HPC-SL, and HPC-L), methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose Hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), 4 with ethylene oxide and formaldehyde - (1,1,3,3-Tetramethylbutyl)-phenol polymers (also known as tetratypol, superione and triton), poloxamers (for example, Pluronics F68 (registered trademark) and F108 (registered trademark) trademark), which are block copolymers of ethylene oxide and propylene oxide); poloxamines (for example, Tetronic 908 (registered trademark), also known as Poloxamine 908 (registered trademark), which are made of propylene oxide and epoxy Tetrafunctional block copolymers obtained by the sequential addition of ethane to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)); charged phospholipids such as dimyristoylphosphatidylglycerol, sulfosuccinic acid di Octyl esters (DOSS); Tetronic 1508 (registered trademark) (T-1508) (BASF Wyandotte Corporation), dialkyl esters of sodium sulfosuccinate (for example, Aerosol OT (registered trademark), which is a Dioctyl ester (American Cyanamid)); Duponol P (registered trademark), which is sodium lauryl sulfate (DuPont); Tritons X-200 (registered trademark), which is alkyl aryl polyether sulfonate ( Rohm and Haas); Crodesta s F-110 (registered trademark), which is a mixture of sucrose stearate and sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin- 10G (registered trademark) or Surfactant 10-G (registered trademark) (Olin Chemicals, Stamford, Conn.); CrodestasSL-40 (registered trademark) (Croda, Inc.); and SA9OHCO, which is C18 H37 CH2 ( CON(CH3 ))-CH2 (CHOH)4 (CH2 OH)2 (Eastman Kodak Co.); Decanoyl-N-methylglucamide; n-Decanyl-β-D-glucopyranoside ; n-decyl-β-D-maltopyranoside; n-dodecyl-β-D-glucopyranoside; n-dodecyl-β-D-maltoside; heptanoyl-N- Methylglucamide; n-heptyl-β-D-glucopyranoside; n-heptyl-β-D-thioglucopyranoside; n-hexyl-β-D-glucopyranoside; nonanoyl-N -Methylglucamide; n-Nonyl-β-D-glucopyranoside; Octanoyl-N-methylglucamide; n-Octyl-β-D-glucopyranoside; Octyl-β -D-thioglucopyranoside; and the like.
这些悬浮剂的大多数是已知的药物赋形剂，并且在由The AmericanPharmaceutical Association和The Pharmaceutical Society of GreatBritain联合出版的Handbook of Pharmaceutical Excipients(药物赋形剂手册)(The Pharmaceutical Press，1986)中详细说明，将其特别引入本文以供参考。这些悬浮剂是市售的，并且/或者可通过本领域中公知的技术制造。Most of these suspensions are known pharmaceutical excipients and are detailed in the Handbook of Pharmaceutical Excipients (The Pharmaceutical Press, 1986), jointly published by The American Pharmaceutical Association and The Pharmaceutical Society of Great Britain. description, which is expressly incorporated herein by reference. These suspension concentrates are commercially available and/or may be manufactured by techniques well known in the art.
在本发明中，优选使用羧甲基纤维素或其盐、羟丙基纤维素、羟丙基乙基纤维素、羟丙基甲基纤维素、或聚乙烯基吡咯烷酮作为载体的悬浮剂。羧甲基纤维素(以下有时称为“CMC”)或其盐(优选钠盐(以下有时称为“CMCNa”))的使用，即使当第二次粉碎步骤中的粉碎反复进行或长时间进行时，特别地确保防止过度粉碎使其中平均粒径小于1μm。In the present invention, a suspending agent using carboxymethylcellulose or a salt thereof, hydroxypropylcellulose, hydroxypropylethylcellulose, hydroxypropylmethylcellulose, or polyvinylpyrrolidone as a carrier is preferable. The use of carboxymethylcellulose (hereinafter sometimes referred to as "CMC") or its salt (preferably sodium salt (hereinafter sometimes referred to as "CMCNa")), even when the pulverization in the second pulverization step is repeated or carried out for a long time When, in particular, ensure that excessive pulverization is prevented so that the average particle size thereof is less than 1 μm.
羧甲基纤维素或其钠盐的粘度范围可适当地选自宽范围。一般来说，4％水溶液在25℃下的粘度优选为约20至400cps，尤其是约50至200cps。The viscosity range of carboxymethylcellulose or its sodium salt can be appropriately selected from a wide range. In general, the viscosity of a 4% aqueous solution at 25°C is preferably about 20 to 400 cps, especially about 50 to 200 cps.
如果需要，本发明的载体可含有填充剂(也称为低温/冻干保护剂)或等渗剂。基于无菌可注射制剂(本发明的阿立哌唑悬浮液)的总重量，该试剂的存在量在约1至约10wt％的范围内，优选约1.5至约8wt％，更优选约2至约5wt％。适合用于本发明的填充剂或等渗剂的实例包括但不限于下列的一种、两种或多种：甘露醇、蔗糖、麦芽糖、木糖醇、葡萄糖、淀粉、山梨醇等，对于平均粒径为约1微米或以上的制剂优选甘露醇。The carriers of the invention may, if desired, contain bulking agents (also known as cryo/lyoprotectants) or isotonic agents. The agent is present in an amount ranging from about 1 to about 10 wt%, preferably from about 1.5 to about 8 wt%, more preferably from about 2 to about 5 wt%. Examples of fillers or isotonic agents suitable for use in the present invention include, but are not limited to, one, two or more of the following: mannitol, sucrose, maltose, xylitol, glucose, starch, sorbitol, etc., for the average Mannitol is preferred for formulations having a particle size of about 1 micron or greater.
根据需要，本发明的载体可含有缓冲液。缓冲液的用量将阿立哌唑的水悬浮液的pH调节至约6至约8，优选大约7。为了达到此pH，基于无菌可注射制剂的总重量(本发明的阿立哌唑悬浮液)，根据类型，缓冲液的用量通常在约0.02至约2wt％的范围内，优选约0.03至约0.1wt％。适合用于本发明的缓冲液的实例包括但不限于下列的一种、两种或多种：磷酸钠、磷酸钾或TRIS缓冲液，优选磷酸钠。The carrier of the present invention may contain a buffer as necessary. The amount of buffer used is to adjust the pH of the aqueous suspension of aripiprazole to about 6 to about 8, preferably about 7. To achieve this pH, the amount of buffer used is usually in the range of about 0.02 to about 2 wt%, preferably about 0.03 to about 0.1 wt%. Examples of buffers suitable for use in the present invention include, but are not limited to, one, two or more of the following: sodium phosphate, potassium phosphate or TRIS buffer, preferably sodium phosphate.
本发明的载体可任选地包括pH调节剂，其用量将阿立哌唑的水悬浮液的pH调节至约6至约7.5的范围，优选大约7，并且可以是酸或碱，取决于冻干阿立哌唑的水悬浮液的pH需要被提高还是降低以达到所需的大约7的中性pH。因此，当pH需要降低时，可采用酸性pH调节剂，诸如盐酸或乙酸，优选盐酸。当pH需要提高时，将采用碱性pH调节剂，诸如氢氧化钠、氢氧化钾、氧化镁或氢氧化镁，优选氢氧化钠。The carrier of the present invention may optionally include a pH adjusting agent in an amount to adjust the pH of the aqueous suspension of aripiprazole to the range of about 6 to about 7.5, preferably about 7, and may be acidic or alkaline, depending on the pH of the aqueous suspension. Whether the pH of the aqueous suspension of dry aripiprazole needs to be raised or lowered to achieve the desired neutral pH of about 7. Thus, when the pH needs to be lowered, an acidic pH adjuster, such as hydrochloric acid or acetic acid, preferably hydrochloric acid, can be used. When the pH needs to be increased, an alkaline pH adjuster such as sodium hydroxide, potassium hydroxide, magnesium oxide or hydroxide, preferably sodium hydroxide, will be employed.
本发明的制造方法Manufacturing method of the present invention
本发明的制造方法描述如下。The production method of the present invention is described below.
如上所述，本发明提供了制造阿立哌唑悬浮液的方法，该方法包括以下的步骤：As mentioned above, the present invention provides a method for manufacturing aripiprazole suspension, the method comprising the following steps:
(a)将散装阿立哌唑与载体混合以形成初级悬浮液；(a) mixing bulk aripiprazole with a carrier to form a primary suspension;
(b)使初级悬浮液经受第一次粉碎以形成二级悬浮液；以及(b) subjecting the primary suspension to a first comminution to form a secondary suspension; and
(c)使二级悬浮液经受第二次粉碎以形成最终悬浮液。(c) Subjecting the secondary suspension to a second comminution to form the final suspension.
根据本发明的一个优选实施方式，提供如下方法：一种制造其中阿立哌唑具有1至10μm、优选1至5μm、更优选2至4μm、最优选约2至3μm的平均粒径的无菌阿立哌唑悬浮液的方法，该方法包括以下的步骤：According to a preferred embodiment of the present invention there is provided a method for the manufacture of sterile aripiprazole wherein the aripiprazole has an average particle size of 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably about 2 to 3 μm The method for aripiprazole suspension, the method comprises the following steps:
(A)将无菌散装阿立哌唑与无菌载体混合以形成无菌初级悬浮液；(A) mixing sterile bulk aripiprazole with a sterile carrier to form a sterile primary suspension;
(B)使用高剪切粉碎机、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、或高压喷射式乳化分散机，使无菌初级悬浮液经受第一次粉碎以形成无菌二级悬浮液；以及(B) Subjecting the sterile primary suspension to a first comminuted to form a sterile secondary suspension; and
(C)使用高压喷射式乳化分散机使无菌二级悬浮液经受第二次粉碎以形成无菌的最终悬浮液。(C) Subject the sterile secondary suspension to a second comminution using a high-pressure jet emulsifying disperser to form a sterile final suspension.
在进行本发明的制备无菌阿立哌唑悬浮液的方法时，需要每一物品都是无菌的，使得无菌阿立哌唑和无菌载体无菌地混合以形成无菌悬浮液。In performing the method of the present invention for preparing a sterile aripiprazole suspension, each item is required to be sterile such that sterile aripiprazole and a sterile carrier are aseptically mixed to form a sterile suspension.
然而，当在获得所需的阿立哌唑悬浮液后能够进行灭菌时，在包括上述步骤(A)、(B)和(C)的方法中没有必要使用无菌阿立哌唑和无菌载体。However, when the desired suspension of aripiprazole can be sterilized, it is not necessary to use sterile aripiprazole and sterile Bacteria carrier.
(A)将无菌散装阿立哌唑与无菌载体混合以形成无菌初级悬浮液的步(A) Step of mixing sterile bulk aripiprazole with a sterile carrier to form a sterile primary suspension骤step
此步骤(A)包括下列的步骤(A-1)、(A-2)和(A-3)。This step (A) includes the following steps (A-1), (A-2) and (A-3).
(A-1)制备无菌散装阿立哌唑的步骤(A-1) Steps for preparing sterile bulk aripiprazole
此步骤通常制备含有10％或更多的粒径为100μm或更大的阿立哌唑颗粒，并具有20μm至1000μm的平均粒径的无菌散装阿立哌唑，优选平均粒径为100μm以上、特别优选110μm至1000μm、最优选200μm至400μm的无菌散装阿立哌唑。This step generally produces sterile bulk aripiprazole containing 10% or more of aripiprazole particles having a particle size of 100 μm or larger and having an average particle size of 20 μm to 1000 μm, preferably an average particle size of 100 μm or more , particularly preferably sterile bulk aripiprazole of 110 μm to 1000 μm, most preferably 200 μm to 400 μm.
将散装阿立哌唑灭菌的方法不受限制，并且可选自许多方法，包括无菌结晶、高压釜灭菌、气体灭菌和辐射灭菌。其中，优选无菌结晶。The method of sterilizing bulk aripiprazole is not limited and may be selected from a number of methods including aseptic crystallization, autoclave sterilization, gas sterilization, and radiation sterilization. Among them, sterile crystals are preferred.
无菌结晶是其中通过将阿立哌唑溶解在溶剂中而制备的溶液通过过滤除菌等灭菌，然后进行结晶的工艺。可以不受限制地使用许多此类工艺，诸如连续结晶法或分批结晶法。The aseptic crystallization is a process in which a solution prepared by dissolving aripiprazole in a solvent is sterilized by filtration sterilization or the like, and then subjected to crystallization. Many such processes can be used without limitation, such as continuous crystallization or batch crystallization.
高压釜灭菌、气体灭菌或辐射灭菌可根据能够对阿立哌唑灭菌的常规方法来进行。Autoclave sterilization, gas sterilization, or radiation sterilization can be performed according to conventional methods capable of sterilizing aripiprazole.
无菌阿立哌唑的晶型已知以一水合物、水合物A、酐晶体B、酐晶体C、酐晶体D、酐晶体E、酐晶体F和酐晶体G等的形式存在，所有这些晶型都可用于本发明的制剂中。其中，最优选一水合物和酐晶体B。The crystalline form of sterile aripiprazole is known to exist in the form of monohydrate, hydrate A, anhydride crystal B, anhydride crystal C, anhydride crystal D, anhydride crystal E, anhydride crystal F and anhydride crystal G, etc., all of which Both crystalline forms can be used in the formulations of the invention. Among them, monohydrate and anhydride crystals B are most preferred.
(A-2)制备用于无菌散装阿立哌唑的无菌载体的步骤(A-2) Procedure for preparing a sterile carrier for sterile bulk aripiprazole
通过将上述的悬浮剂、和任选的填充剂或等渗剂、缓冲液和pH调节剂均一地溶解在注射用水中，并且将得到的载体溶液灭菌而制备用于无菌散装阿立哌唑的载体。By uniformly dissolving the above-mentioned suspending agent, and optional fillers or isotonic agents, buffers and pH regulators in water for injection, and sterilizing the obtained carrier solution, it is prepared for use in sterile bulk aripipr azole carrier.
用于对载体溶液灭菌的方法不受限制，但优选用滤器过滤。滤器的孔径优选为约0.2μm。The method used to sterilize the carrier solution is not limited, but filtration with a filter is preferred. The pore size of the filter is preferably about 0.2 μm.
(A-3)将无菌阿立哌唑与无菌载体混合以形成无菌初级悬浮液的步骤(A-3) Step of mixing sterile aripiprazole with a sterile carrier to form a sterile primary suspension
无菌散装阿立哌唑和无菌载体被无菌混合以形成无菌初级悬浮液。无菌混合工艺不受限制，只要其是已知的无菌搅拌技术，诸如使用具有推进器的机械搅拌装置的无菌混合方法。混合时的条件不受限制。例如，优选的搅拌条件为，粉末颗粒在载体中混合而不发泡。Sterile bulk aripiprazole and a sterile carrier are aseptically mixed to form a sterile primary suspension. The aseptic mixing process is not limited as long as it is a known aseptic mixing technique, such as an aseptic mixing method using a mechanical stirring device with a propeller. Conditions at the time of mixing are not limited. For example, preferred agitation conditions are such that the powder particles are mixed in the carrier without foaming.
要在无菌载体中分散的无菌散装阿立哌唑的浓度可适当地选自宽范围，但通常为约10至400mg/ml，优选50至250mg/ml，最优选约100mg/ml。The concentration of sterile bulk aripiprazole to be dispersed in the sterile vehicle may suitably be selected from a wide range, but will generally be from about 10 to 400 mg/ml, preferably from 50 to 250 mg/ml, most preferably about 100 mg/ml.
步骤(A-3)中的混合过程可在常压(大气压)或加压下进行。不象专利文件3，不需要采用真空或减压条件。在加压时，通常混合过程优选在约0至0.3MPa的表压下进行。步骤(A-3)中优选的温度条件为约5至80℃，尤其是约10至40℃。不象专利文件1，不需要采用散装阿立哌唑的熔点或之上的温度。The mixing process in step (A-3) can be performed under normal pressure (atmospheric pressure) or under increased pressure. Unlike Patent Document 3, it is not necessary to employ vacuum or reduced pressure conditions. When pressurized, generally the mixing process is preferably carried out at a gauge pressure of about 0 to 0.3 MPa. Preferred temperature conditions in step (A-3) are about 5 to 80°C, especially about 10 to 40°C. Unlike Patent Document 1, there is no need to use a temperature at or above the melting point of bulk aripiprazole.
(B)使用高剪切粉碎机(例如高剪切高速搅拌机)、将剪切力施加于(B) Using a high-shear pulverizer (such as a high-shear high-speed mixer), apply shear force to待加工的材料的分散机、胶体研磨机、超声分散机、或高压喷射式乳Disperser, colloid mill, ultrasonic disperser, or high-pressure jet emulsifier for the material to be processed化分散机(例如高压均质器)，使无菌初级悬浮液经受第一次粉碎以形A dispersing machine (such as a high-pressure homogenizer) to subject the sterile primary suspension to a first comminution to form成无菌二级悬浮液的步骤Steps into a sterile secondary suspension
通过第一次粉碎步骤，阿立哌唑的粒径减小至所需水平。在第一次粉碎步骤中使用的粉碎机的实例包括可适当地产生具有目标粒径的颗粒的粉碎机，诸如高剪切粉碎机、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机(粉碎机)、或高压喷射式乳化分散机(例如高压均质器)。优选使用高剪切粉碎机或将剪切力施加于待加工的材料的分散机。作为此类高剪切粉碎机，例如，高剪切高速搅拌机，有许多市售产品，诸如“Clearmix”(商品名，由M-Technique Co.，Ltd.生产)。然而，它们不受限制，只要它们是气密的和不发泡的高剪切粉碎机。Through the first pulverization step, the particle size of aripiprazole is reduced to the desired level. Examples of the pulverizer used in the first pulverization step include a pulverizer that can appropriately produce particles having a target particle size, such as a high-shear pulverizer, a disperser that applies a shearing force to the material to be processed, a colloid A grinder, an ultrasonic disperser (crusher), or a high-pressure jet emulsification disperser (such as a high-pressure homogenizer). Preference is given to using a high shear pulverizer or a disperser which applies a shear force to the material to be processed. As such a high-shear pulverizer, for example, a high-shear high-speed mixer, there are many commercially available products such as "Clearmix" (trade name, manufactured by M-Technique Co., Ltd.). However, they are not limited as long as they are airtight and non-foaming high shear pulverizers.
使用高剪切高速搅拌机进行粉碎的条件可以是可适当地获得目标粒径的条件。目标粒径可以是在随后的第二次粉碎步骤中使用的均质器的流路不被堵塞的粒径。典型条件可以是平均粒径被减小至约5至100μm，优选5至50μm。The conditions for pulverization using a high-shear high-speed mixer may be conditions under which the target particle size can be appropriately obtained. The target particle size may be a particle size at which the flow path of the homogenizer used in the subsequent second pulverization step is not clogged. Typical conditions may be that the average particle size is reduced to about 5 to 100 μm, preferably 5 to 50 μm.
在第一次粉碎步骤中，优选使用上述装置以通常5至50m/s、优选10至40m/s、更优选约15至35m/s的旋转叶片(转子)圆周速度进行粉碎。以此圆周速度能特别有效地操作高剪切粉碎机，诸如高剪切高速搅拌机(例如，商品名为Clearmix的市售产品)。例如，使用Clearmix CLM-1.5S以28.3m/s的圆周速度使初级悬浮液(4L，实验室规模)经受第一次粉碎，以及使用Clearmix CLM-9S或ClearmixCLM-15S以28.3m/s的圆周速度使初级悬浮液(40L，放大规模)经受第一次粉碎，获得具有10至20μm的平均粒径的二级悬浮液。In the first crushing step, crushing is preferably carried out using the above-mentioned apparatus at a peripheral speed of the rotating blade (rotor) of usually 5 to 50 m/s, preferably 10 to 40 m/s, more preferably about 15 to 35 m/s. High shear pulverizers, such as high shear high speed mixers (eg, commercially available under the tradename Clearmix) can be operated particularly efficiently at this peripheral speed. For example, a primary suspension (4 L, laboratory scale) was subjected to first comminution using Clearmix CLM-1.5S at a peripheral speed of 28.3 m/s, and a peripheral speed of 28.3 m/s using Clearmix CLM-9S or Clearmix CLM-15S Velocity The primary suspension (40 L, scale-up) was subjected to a first comminution to obtain a secondary suspension with an average particle size of 10 to 20 μm.
步骤(B)中的温度条件为约5至80℃，尤其是约10至40℃。The temperature condition in the step (B) is about 5 to 80°C, especially about 10 to 40°C.
可使用将剪切力施加于待分散的材料的分散机，即在加工期间将剪切力施加于阿立哌唑颗粒的分散装置，代替高剪切高速搅拌机。此类分散机有许多市售产品，包括将剪切力施加于待加工的材料的分散机(商品名：“T-50Basic”，由IKA Japan，Inc.制造)。通过这些分散机进行粉碎的条件可以是可适当地获得目标粒径的条件。目标粒径可以是在随后的第二次粉碎步骤中使用的均质器的流路不被堵塞的粒径。典型条件可以是平均粒径被减小至约5至100μm，优选5至50μm。A disperser that applies shear force to the material to be dispersed, that is, a disperser that applies shear force to aripiprazole particles during processing, may be used instead of a high-shear high-speed mixer. There are many commercially available products of such a disperser, including a disperser (trade name: "T-50Basic", manufactured by IKA Japan, Inc.) that applies a shearing force to a material to be processed. The conditions for pulverization by these dispersers may be conditions under which the target particle size can be appropriately obtained. The target particle size may be a particle size at which the flow path of the homogenizer used in the subsequent second pulverization step is not clogged. Typical conditions may be that the average particle size is reduced to about 5 to 100 μm, preferably 5 to 50 μm.
还可在与上面所述基本相同的条件下使用胶体研磨机、超声分散机(粉碎机)或高压喷射式乳化分散机。It is also possible to use a colloid mill, an ultrasonic disperser (disintegrator), or a high-pressure jet emulsification disperser under substantially the same conditions as described above.
步骤(B)中的粉碎可在常压(大气压)或加压下进行。不象专利文件3，不需要采用真空或减压条件。在加压时，通常混合过程优选在约0至0.3MPa的表压下进行。Pulverization in step (B) can be performed under normal pressure (atmospheric pressure) or under increased pressure. Unlike Patent Document 3, it is not necessary to employ vacuum or reduced pressure conditions. When pressurized, generally the mixing process is preferably carried out at a gauge pressure of about 0 to 0.3 MPa.
(C)使用高压喷射式乳化分散机(例如高压均质器)使无菌二级悬浮(C) Use a high-pressure jet emulsification disperser (such as a high-pressure homogenizer) to make the sterile secondary suspension液经受第二次粉碎以形成无菌的最终悬浮液的步骤liquid undergoes a second crushing step to form a sterile final suspension
通过第二次粉碎步骤，阿立哌唑的粒径被减小至所需的水平。在第二次粉碎步骤中使用的粉碎机的实例包括在高压下处理工艺液体的高压喷射式乳化分散机。优选的高压喷射式乳化分散机是高压均质器，其中通过调节喷射部中特别设计的阀门，将泵压(pump-pressurized)工艺液体作为射流在高压下喷射。此类装置的典型型号包括EmulsiFlex(由Avestin制造)和由APV、NIRO SOAVI或Sanwa Machine Co.Inc.制造的高压均质器。还可使用其他分散机，其中工艺液体在高压下通过以如下方向配置的各种形状的孔，该方向使工艺液体相互碰撞。此类装置的典型型号包括Microfluidizer(由Microfluidics制造)、Starburst(Sugino Machine Ltd.)，和Nanomizer(Yoshida Kikai Co.，Ltd.)等。The particle size of aripiprazole is reduced to the desired level by the second pulverization step. Examples of the pulverizer used in the second pulverization step include a high-pressure jet type emulsification disperser that treats a process liquid under high pressure. A preferred high-pressure jet emulsifying disperser is a high-pressure homogenizer, in which a pump-pressurized process liquid is jetted under high pressure as a jet by adjusting a specially designed valve in the jetting section. Typical models of such devices include EmulsiFlex (manufactured by Avestin) and high pressure homogenizers manufactured by APV, NIRO SOAVI or Sanwa Machine Co. Inc. Other dispersing machines may also be used in which process liquids are passed under high pressure through holes of various shapes arranged in a direction that causes the process liquids to collide with each other. Typical models of such devices include Microfluidizer (manufactured by Microfluidics), Starburst (Sugino Machine Ltd.), and Nanomizer (Yoshida Kikai Co., Ltd.) and the like.
高压均质器的粉碎压力优选为约300至1000bar，更优选为约300至600bar。高压均质器的入口温度可以适当地选自宽范围，但通常为约1至70℃，优选约5至40℃。The crushing pressure of the high pressure homogenizer is preferably about 300 to 1000 bar, more preferably about 300 to 600 bar. The inlet temperature of the high-pressure homogenizer can be appropriately selected from a wide range, but is generally about 1 to 70°C, preferably about 5 to 40°C.
通过在上述条件下进行第二次粉碎步骤，在最终悬浮液中阿立哌唑的平均粒径优选被调节至约1至10μm，优选1至5μm，更优选2至4μm，最优选2至3μm。具有2至3μm的平均粒径的阿立哌唑悬浮液是很有用的，因为其具有优异的吸收特征，并在制造过程中不发生沉淀。The average particle size of aripiprazole in the final suspension is preferably adjusted to about 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably 2 to 3 μm by performing the second pulverization step under the above conditions . Aripiprazole suspensions having an average particle size of 2 to 3 μm are useful because they have excellent absorption characteristics and do not precipitate during the manufacturing process.
步骤(C)的第二次粉碎步骤可通过使悬浮液经过高压均质器多次来进行。在此情况下，可采用不连续传送(discrete-pass)法和再循环法，得到类似结果(参见后面所述的实施例1-5和实施例6)。两种系统也可组合在一起(参见后面所述的实施例7)。The second crushing step of step (C) can be carried out by passing the suspension through a high-pressure homogenizer several times. In this case, the discrete-pass method and the recirculation method can be used with similar results (see Examples 1-5 and Example 6 described later). Both systems can also be combined (see Example 7 described below).
不连续传送法具体地是指如下的加工悬浮液的方法：通过使悬浮液的多个部分经过例如高压均质器，直至其所有部分被加工，同时回收已加工的悬浮液。当悬浮液通过不连续传送法被加工多次时，回收的悬浮液通过如下方式加工：使已回收的悬浮液的多个部分经过高压均质器，直至其所有部分被加工，同时回收已加工的悬浮液，并且重复此步骤。The discontinuous transfer method refers in particular to a method of processing a suspension by passing parts of the suspension, for example, through a high-pressure homogenizer until all parts thereof are processed, while recovering the processed suspension. When the suspension is processed multiple times by the discontinuous transfer method, the recovered suspension is processed by passing parts of the recovered suspension through a high-pressure homogenizer until all parts thereof are processed while recovering the processed suspension, and repeat this step.
再循环法具体地是指如下方法，其中与例如高压均质器的入口连接的含有悬浮液的罐或容器，还经回收管线与均质器的出口连接，并且罐或容器中的悬浮液被均质器连续加工而不被回收，使得已加工的悬浮液通过回收管线回收至罐或容器中，在此它们与未加工的悬浮液混合，使混合物连续地经过均质器，并且由此悬浮液被循环加工。The recirculation method specifically refers to a method in which a tank or container containing a suspension connected, for example, to the inlet of a high-pressure homogenizer is also connected to an outlet of the homogenizer via a recovery line, and the suspension in the tank or container is Homogenizers process continuously without being recycled, so that the processed suspension is recycled through a recovery line to a tank or vessel where they are mixed with raw suspension, the mixture is passed continuously through the homogenizer, and thus suspended The liquid is recycled.
不象专利文件3，步骤(C)中的粉碎不需要真空或减压条件。Unlike Patent Document 3, the pulverization in step (C) does not require vacuum or reduced pressure conditions.
当在第一次和第二次粉碎步骤中都使用高压均质器时，包括本发明的上述步骤(A)至(C)的制造方法的步骤(B)和(C)优选地分别如下面的步骤(BB)和(CC)所示来进行。When high-pressure homogenizers are used in both the first and second crushing steps, steps (B) and (C) of the manufacturing method including the above-mentioned steps (A) to (C) of the present invention are preferably as follows, respectively Proceed as indicated in steps (BB) and (CC).
步骤(BB)step (BB)
本发明的步骤(BB)是第一次粉碎步骤，其中在步骤(A)中获得的无菌初级悬浮液使用高压均质器在50至200bar、优选70至150bar的粉碎压力下粉碎，以获得二级悬浮液。发现当采用此步骤时，能解决上面提到的堵塞问题。Step (BB) of the present invention is a first comminution step in which the sterile primary suspension obtained in step (A) is comminuted using a high-pressure homogenizer at a comminution pressure of 50 to 200 bar, preferably 70 to 150 bar, to obtain secondary suspension. It was found that when this procedure was employed, the clogging problem mentioned above could be resolved.
换句话说，在50至200bar、优选70至150bar的范围内的粉碎压力下，使用高压均质器能防止高压均质器的流路堵塞。In other words, using a high-pressure homogenizer can prevent clogging of a flow path of the high-pressure homogenizer at a crushing pressure in the range of 50 to 200 bar, preferably 70 to 150 bar.
高压均质器的入口温度可适当地选自宽范围，但通常为约1至50℃，优选约5至40℃。The inlet temperature of the high-pressure homogenizer can be appropriately selected from a wide range, but is generally about 1 to 50°C, preferably about 5 to 40°C.
以此方式获得无菌二级悬浮液。In this way a sterile secondary suspension is obtained.
步骤(CC)step (CC)
本发明的步骤(CC)是第二次粉碎步骤，其中步骤(BB)中获得的无菌二级悬浮液使用高压均质器在200至1000bar的粉碎压力下粉碎以获得无菌的最终悬浮液。此步骤提供具有所需的1至10μm、优选1至5μm、更优选2至4μm、最优选约2.5μm的平均粒径的阿立哌唑悬浮液。Step (CC) of the present invention is a second comminution step, wherein the sterile secondary suspension obtained in step (BB) is comminuted using a high pressure homogenizer at a comminution pressure of 200 to 1000 bar to obtain a sterile final suspension . This step provides an aripiprazole suspension with the desired average particle size of 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably about 2.5 μm.
与步骤(BB)中的粉碎压力相比，在步骤(CC)中，高压均质器的粉碎压力需要被提高。通常，步骤(CC)中的粉碎压力优选被设定为比步骤(BB)高约100至900bar，尤其是约200至500bar。In step (CC), the crushing pressure of the high pressure homogenizer needs to be increased compared to the crushing pressure in step (BB). Generally, the crushing pressure in step (CC) is preferably set to be about 100 to 900 bar, especially about 200 to 500 bar, higher than in step (BB).
步骤(CC)中高压均质器的优选粉碎压力为200至1000bar，尤其是约300至600bar。The preferred crushing pressure of the high pressure homogenizer in step (CC) is 200 to 1000 bar, especially about 300 to 600 bar.
当在步骤(CC)中进行多次粉碎时，粉碎压力还可在200至1000bar的范围内逐步提高。在此情况下，最终压力优选为约300至1000bar，更优选约300至600bar。When comminution is carried out several times in step (CC), the comminution pressure can also be gradually increased within the range of 200 to 1000 bar. In this case, the final pressure is preferably about 300 to 1000 bar, more preferably about 300 to 600 bar.
高压均质器的入口温度适当地选自宽范围，但通常为约1至50℃，优选为约5至40℃。The inlet temperature of the high-pressure homogenizer is properly selected from a wide range, but is generally about 1 to 50°C, preferably about 5 to 40°C.
步骤(CC)的第二次粉碎步骤可通过使悬浮液经过高压均质器多次来进行。可采用上述的不连续传送法和再循环法，得到类似的结果。两种方法还可组合在一起。The second pulverization step of step (CC) can be carried out by passing the suspension through a high-pressure homogenizer several times. Similar results can be obtained using the discontinuous delivery and recirculation methods described above. Both methods can also be combined.
不象专利文件3，步骤(CC)中的粉碎不需要真空或减压条件。Unlike Patent Document 3, the pulverization in step (CC) does not require vacuum or reduced pressure conditions.
在本发明中，能够通过进行原位清洗(CIP)和原位灭菌(SIP)对本发明中使用的机器(诸如高剪切粉碎机、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、和高压喷射式乳化分散机)的与液体接触的表面进行清洗和灭菌。还能够在线灭菌。可使用水、热水、碱性水、酸性水或有机溶剂进行CIP，任选地添加常规使用的一种或多种清洗剂，诸如碱性洗涤剂、中性洗涤剂和酸性洗涤剂。可使用纯蒸汽、高压高温水等进行SIP。In the present invention, machines used in the present invention (such as high-shear pulverizers, dispersers that apply shear force to materials to be processed, Colloid mill, ultrasonic disperser, and high-pressure jet emulsification disperser) are cleaned and sterilized on the surface in contact with the liquid. In-line sterilization is also possible. CIP may be performed using water, hot water, alkaline water, acidic water, or an organic solvent, optionally adding one or more of conventionally used cleaning agents, such as alkaline detergents, neutral detergents, and acidic detergents. SIP can be performed using pure steam, high-pressure high-temperature water, etc.
因此，通过在步骤(b)中使用其表面与已经灭菌的液体接触的高剪切粉碎机(诸如高剪切高速搅拌机)、将剪切力施加于待加工的材料的分散机、胶体研磨机、超声分散机、或高压喷射式乳化分散机(诸如高压均质器)，将在步骤(a)中产生的无菌初级阿立哌唑悬浮液无菌粉碎，以形成无菌二级悬浮液，并在步骤(c)中使用其表面与已经灭菌的液体接触的高压喷射式乳化分散机(诸如高压均质器)将得到的无菌二级悬浮液无菌粉碎，而获得其中阿立哌唑具有1至10μm的平均粒径的无菌阿立哌唑悬浮液。Therefore, by using a high-shear pulverizer (such as a high-shear high-speed mixer) whose surface is in contact with the liquid that has been sterilized, a disperser that applies a shear force to the material to be processed, a colloid mill machine, ultrasonic dispersing machine, or high-pressure jet emulsifying dispersing machine (such as high-pressure homogenizer), the sterile primary aripiprazole suspension produced in step (a) is aseptically pulverized to form a sterile secondary suspension liquid, and in step (c), use a high-pressure jet emulsification disperser (such as a high-pressure homogenizer) whose surface is in contact with the sterilized liquid to aseptically pulverize the obtained sterile secondary suspension to obtain the Ripiprazole Sterile aripiprazole suspension having an average particle size of 1 to 10 μm.
阿立哌唑水悬浮液Aripiprazole aqueous suspension
通过本发明的制造方法制造的阿立哌唑水悬浮液中的阿立哌唑具有1至10μm、优选1至5μm、更优选2至4μm、最优选约2至3μm的平均粒径。Aripiprazole in the aqueous suspension of aripiprazole produced by the production method of the present invention has an average particle diameter of 1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm, most preferably about 2 to 3 μm.
根据本发明的制造方法，不管散装阿立哌唑的平均粒径有多大，最终获得的悬浮液中阿立哌唑的平均粒径都被控制在上述范围内。因此，该方法具有极大的优点：对无菌散装粉末的制造的限制很少；当使用具有大粒径的散装粉末时，在制备悬浮液期间很少发生气泡夹带，并且消泡过程很便利；不需要减压，且明显地减少了外界空气污染的可能性。According to the production method of the present invention, no matter how large the average particle diameter of the bulk aripiprazole is, the average particle diameter of the aripiprazole in the finally obtained suspension is controlled within the above range. Therefore, this method has great advantages: there are few restrictions on the manufacture of sterile bulk powders; when bulk powders with large particle sizes are used, air bubble entrainment rarely occurs during the preparation of suspensions, and the defoaming process is facilitated ; No decompression is required, and the possibility of external air pollution is significantly reduced.
根据本发明的制造方法，可制造不含粗阿立哌唑颗粒的均一的最终悬浮液，并且因此，如果需要，获得的最终悬浮液(即，所需的阿立哌唑悬浮液)可被过滤以去除外来物质。要使用的滤器具有的孔径要使滤器具有10至225μm、优选20至70μm的公称过滤精度。因此，本发明的制造方法可进一步包括用具有10至225μm的公称过滤精度的滤器过滤步骤(c)中获得的最终悬浮液的步骤。According to the production method of the present invention, a uniform final suspension free of coarse aripiprazole particles can be produced, and thus, if necessary, the obtained final suspension (i.e., the desired aripiprazole suspension) can be Filter to remove foreign material. The filters to be used have a pore size such that the filters have a nominal filtration rating of 10 to 225 μm, preferably 20 to 70 μm. Therefore, the manufacturing method of the present invention may further comprise a step of filtering the final suspension obtained in step (c) with a filter having a nominal filtration degree of 10 to 225 μm.
得到的最终悬浮液(即，所需的阿立哌唑悬浮液)优选具有约10至400mg/ml、更优选约50至250mg/ml、最优选100mg/ml的浓度。The resulting final suspension (ie the desired aripiprazole suspension) preferably has a concentration of about 10 to 400 mg/ml, more preferably about 50 to 250 mg/ml, most preferably 100 mg/ml.
通过本发明的制造方法获得的无菌阿立哌唑悬浮液，作为注射制剂例如经肌内和皮下给药。The sterile aripiprazole suspension obtained by the production method of the present invention is administered as an injection preparation such as intramuscularly and subcutaneously.
制造冻干制剂的方法Method for manufacturing lyophilized formulations
通过上述方法获得的无菌阿立哌唑悬浮液可被冻干以制造冻干制剂。The sterile aripiprazole suspension obtained by the above method can be lyophilized to produce a lyophilized preparation.
更具体地，最终的阿立哌唑悬浮液可被冻干成所需多形态(无水化物、水合物A、或它们的混合物)的冻干制剂。为了获得阿立哌唑水合物A的冻干制剂，使用一水合物或水合物A作为散装阿立哌唑，并且通过本发明的方法获得的水合物A悬浮液进行下面的冻干周期。More specifically, the final aripiprazole suspension can be lyophilized into a lyophilized formulation of the desired polymorph (anhydrate, hydrate A, or mixtures thereof). In order to obtain a lyophilized formulation of aripiprazole hydrate A, monohydrate or hydrate A is used as bulk aripiprazole, and the hydrate A suspension obtained by the method of the present invention is subjected to the following lyophilization cycle.
冻干周期包括将悬浮液以适当的冷却速率冷却至-20℃至-55℃以使悬浮液冷冻，并且在约0℃以下的温度(优选约0℃至-15℃)在适当的真空(例如约1至100Pa)以适当的持续时间(例如直至获得冻干制剂；一般为约10至100小时)进行干燥步骤。The lyophilization cycle involves cooling the suspension to -20°C to -55°C at a suitable cooling rate to freeze the suspension, and at a temperature below about 0°C (preferably about 0°C to -15°C) under a suitable vacuum ( The drying step is carried out for a suitable duration (eg until a lyophilized formulation is obtained; typically about 10 to 100 hours).
如果需要含有无水形式的阿立哌唑的冻干制剂，使用一水合物或无水晶体形式的阿立哌唑作为散装阿立哌唑，并且通过本发明的方法获得的悬浮液进行下面的冻干周期。冻干周期包括三个步骤(冷冻、初步干燥、二次干燥)。具体地，冻干周期包括将悬浮液以适当的冷却速率冷却至-20℃至-55℃以使悬浮液冷冻；在约0℃以下的温度(优选约0℃至-20℃)在适当的真空(例如约1至100Pa)以适当的持续时间(一般为约10至100小时)进行初步干燥；并且在约0℃以上的温度(优选0℃至60℃)在适当的真空(例如约0.1至20Pa)以适当的持续时间(例如直至获得冻干制剂；一般为约10至100小时)进行二次干燥。If a lyophilized formulation containing aripiprazole in anhydrous form is desired, aripiprazole in monohydrate or anhydrous crystalline form is used as bulk aripiprazole and the suspension obtained by the method of the present invention is subjected to the following freeze-drying dry cycle. The lyophilization cycle consists of three steps (freezing, primary drying, secondary drying). Specifically, the lyophilization cycle includes cooling the suspension to -20°C to -55°C at an appropriate cooling rate to freeze the suspension; Vacuum (for example, about 1 to 100 Pa) carries out preliminary drying with appropriate duration (generally about 10 to 100 hours); to 20 Pa) for a suitable duration (for example until a lyophilized formulation is obtained; typically about 10 to 100 hours) for secondary drying.
由此制造的冻干制剂可很容易地使用注射用水在给药之前立即重新配制成所需的阿立哌唑悬浮液。因此，冻干制剂可用作使用前立即制备的制剂。甚至通过与向制剂中加入注射用水并用手摇动混合物一样简单的重新配制方法，就可获得均一的阿立哌唑悬浮液。The lyophilized formulation thus produced can be easily reconstituted into the desired aripiprazole suspension using water for injection immediately before administration. Therefore, lyophilized preparations can be used as preparations prepared immediately before use. Even by a reconstitution method as simple as adding water for injection to the formulation and shaking the mixture by hand, a homogeneous aripiprazole suspension can be obtained.
实施例Example
下面提供实施例以进一步详细地说明本发明。Examples are provided below to illustrate the present invention in further detail.
在各实施例中，平均粒径是用激光光散射(LLS)衍射粒径分析仪(激光衍射粒径分析仪SALD-3000J，Shimadzu Corp.)测定的体积平均直径。术语“10％直径”、“50％直径”和“90％直径”分别是指在粒径分布中，积分的分布曲线(％)与积分值的10％值相交的点的粒径，与50％值相交的点的粒径，以及与90％值相交的点的粒径。测定条件如下。介质：水；折射率：2.00至0.20i；池：流动池。In each example, the average particle diameter is a volume average diameter measured with a laser light scattering (LLS) diffraction particle size analyzer (laser diffraction particle size analyzer SALD-3000J, Shimadzu Corp.). The terms "10% diameter", "50% diameter" and "90% diameter" respectively refer to the particle diameter at the point where the integrated distribution curve (%) intersects the 10% value of the integrated value in the particle size distribution, and the 50% The particle size at the point where the % value intersects, and the particle size at the point where the 90% value intersects. The measurement conditions are as follows. Medium: Water; Refractive Index: 2.00 to 0.20i; Cell: Flow cell.
在各实施例中，除非另外说明，制备载体和将散装阿立哌唑与载体混合以形成初级悬浮液的步骤均在室温(20至30℃)下进行。除非另外说明，用于粉碎初级悬浮液的第一次粉碎步骤在20至45℃下进行。In each example, the steps of preparing the carrier and mixing bulk aripiprazole with the carrier to form the primary suspension were performed at room temperature (20 to 30° C.) unless otherwise stated. The first comminution step for comminuting the primary suspension was carried out at 20 to 45° C., unless otherwise stated.
在各实施例中使用的高压均质器为市售的高压均质器(商品名“PANDA 2K Type”，由NIRO SOAVI制造)。The high-pressure homogenizer used in each example was a commercially available high-pressure homogenizer (trade name "PANDA 2K Type", manufactured by NIRO SOAVI).
实施例1Example 1
(a)将羧甲基纤维素钠(18.30g)、91.52g甘露醇和1.63g一水合磷酸二氢钠溶解在纯净水中。总重量为2059.2g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。(a) Sodium carboxymethylcellulose (18.30 g), 91.52 g of mannitol and 1.63 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 2059.2g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶制造的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝258μm；10％直径＝99μm；50％直径＝280μm；90％直径＝609μm)分散在得到的滤液(1872g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle diameter of bulk powder = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm) produced by batch crystallization was dispersed in the obtained filtrate (1872g) to form a primary suspension.
使用Three-One Motor(由HEIDON制造)，采用100mm直径叶片以约200至400rpm搅拌来进行制备初级悬浮液的分散工序。(除非另外说明，同样适用于下面的实施例)。The dispersion process for preparing the primary suspension was carried out using a Three-One Motor (manufactured by HEIDON), stirring with a 100 mm diameter blade at about 200 to 400 rpm. (Unless stated otherwise, the same applies to the examples below).
(b)使用高剪切高速搅拌机(商品名：“Clearmix(CLM-1.5S)”，由M Technique Co.，Ltd.生产)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。(b) The primary suspension was pulverized using a high-shear high-speed mixer (trade name: "Clearmix (CLM-1.5S)", manufactured by M Technique Co., Ltd.) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
(c)将获得的二级悬浮液冷却或加热从而将入口温度保持在约10℃、约20℃、约40℃以及约60℃。在600bar下通过不连续传送法使悬浮液经过高压均质器10次而进行粉碎。(c) cooling or heating the obtained secondary suspension so as to maintain the inlet temperature at about 10°C, about 20°C, about 40°C and about 60°C. The suspension was pulverized by passing the suspension 10 times through a high pressure homogenizer at 600 bar by the discontinuous transfer method.
用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表1Table 1
表1表明：Table 1 shows that:
(i)即使当使用由分批结晶生产的散装阿立哌唑一水合物时，在第二次粉碎中(步骤(c))使悬浮液在10至60℃的入口温度下，在00bar下经过高压均质器一次能够制备平均粒径为1至10μm的阿立哌唑悬浮液。(i) Even when using bulk aripiprazole monohydrate produced by batch crystallization, in the second comminution (step (c)) the suspension is brought to an inlet temperature of 10 to 60°C at 00 bar An aripiprazole suspension with an average particle size of 1 to 10 μm can be prepared by passing through a high-pressure homogenizer once.
(ii)在第二次粉碎中(步骤(c))使悬浮液在10至60℃的入口温度下，在600bar下经过高压均质器10次能够制备平均粒径为约2至4μm的阿立哌唑悬浮液。(ii) in the second comminution (step (c)) passing the suspension through a high-pressure homogenizer at 600 bar 10 times at an inlet temperature of 10 to 60° C. enables the preparation of arganum with an average particle size of about 2 to 4 μm. Ripiprazole suspension.
(iii)在第二次粉碎中(步骤(c))使悬浮液在10至40℃的入口温度下，在600bar下经过高压均质器10次能够制备平均粒径为约2至3μm的阿立哌唑悬浮液。(iii) in the second comminution (step (c)) passing the suspension through a high-pressure homogenizer at 600 bar 10 times at an inlet temperature of 10 to 40° C. enables the preparation of arganum with an average particle size of about 2 to 3 μm. Ripiprazole suspension.
这表明甚至使用平均粒径大的散装粉末也获得了具有所需平均粒径(1至10μm，优选1至5μm，更优选2至4μm)的悬浮液，这是本发明的效果之一。This indicates that a suspension having a desired average particle diameter (1 to 10 μm, preferably 1 to 5 μm, more preferably 2 to 4 μm) is obtained even with a bulk powder having a large average particle diameter, which is one of the effects of the present invention.
即使使用无菌散装阿立哌唑和无菌载体也获得了与上面相同的结果。同样也适用于下面的实施例。The same results as above were obtained even with sterile bulk aripiprazole and a sterile vehicle. The same applies to the following examples.
实施例2Example 2
将羧甲基纤维素钠(45.76g)、228.80g甘露醇和4.07g一水合磷酸二氢钠溶解在纯净水中。总重量为5148g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (45.76 g), 228.80 g of mannitol, and 4.07 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 5148g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝239μm；10％直径＝99μm；50％直径＝276μm；90％直径＝632μm)分散在得到的滤液(1872g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm) produced by batch crystallization was dispersed in the obtained filtrate (1872g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却从而将入口温度保持在约20℃，并在300bar、600bar和1000bar下通过不连续传送法使悬浮液经过高压均质器10次而进行粉碎。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The obtained secondary suspension was cooled so as to keep the inlet temperature at about 20° C. and pulverized by passing the suspension 10 times through a high pressure homogenizer by the discontinuous transfer method at 300 bar, 600 bar and 1000 bar. The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表2Table 2
表2表明：Table 2 shows that:
(i)即使当使用由分批结晶生产的散装阿立哌唑一水合物时，使悬浮液在300至1000bar下经过高压均质器一次能够制备平均粒径为1至10μm的阿立哌唑悬浮液。(i) Even when bulk aripiprazole monohydrate produced by batch crystallization is used, passing the suspension through a high-pressure homogenizer at 300 to 1000 bar once can produce aripiprazole having an average particle diameter of 1 to 10 μm suspension.
(ii)使悬浮液在300至1000bar下经过高压均质器10次能够制备平均粒径为2至3μm的阿立哌唑悬浮液。(ii) Passing the suspension through a high pressure homogenizer at 300 to 1000 bar 10 times can prepare an aripiprazole suspension with an average particle diameter of 2 to 3 μm.
(iii)在1000bar下也能制备平均粒径为2至3μm的阿立哌唑悬浮液。然而，可在300至600bar下有效地获得所需的阿立哌唑悬浮液。(iii) Aripiprazole suspensions with an average particle size of 2 to 3 μm can also be prepared at 1000 bar. However, the desired suspension of aripiprazole can be effectively obtained at 300 to 600 bar.
实施例3Example 3
将羧甲基纤维素钠(45.76g)、228.80g甘露醇和4.07g一水合磷酸二氢钠溶解在纯净水中。总重量为5148g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。使用粘度为93cps(4％水溶液，25℃)和187cps(4％水溶液，25℃)的两种羧甲基纤维素钠。Sodium carboxymethylcellulose (45.76 g), 228.80 g of mannitol, and 4.07 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 5148g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter. Two sodium carboxymethylcelluloses with viscosities of 93 cps (4% aqueous solution, 25°C) and 187 cps (4% aqueous solution, 25°C) were used.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；用于研究粘度为93cps的羧甲基纤维素钠的散装粉末的平均粒径＝258μm；10％直径＝99μm；50％直径＝280μm；90％直径＝609μm；用于研究粘度为187cps的羧甲基纤维素钠的散装粉末的平均粒径＝239μm；10％直径＝99μm；50％直径＝276μm；90％直径＝632μm)分散在得到的滤液(1872g)中以形成初级悬浮液。The bulk powder of aripiprazole monohydrate produced by batch crystallization (208 g; average particle diameter = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm; the average particle diameter used to study the bulk powder of sodium carboxymethylcellulose with a viscosity of 187 cps = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm) Disperse in the resulting filtrate (1872 g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对每种初级悬浮液进行粉碎。结果，获得二级悬浮液。Each primary suspension was comminuted with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却从而将入口温度保持在约20℃，并在600bar下通过不连续传送法使悬浮液经过高压均质器10次而进行粉碎。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The obtained secondary suspension was cooled so as to keep the inlet temperature at about 20° C., and comminuted by passing the suspension through a high pressure homogenizer 10 times at 600 bar by discontinuous transfer. The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表3table 3
表3表明CMCNa的粘度差异不影响粉碎作用。Table 3 shows that the viscosity difference of CMCNa does not affect the pulverization.
实施例4Example 4
将羧甲基纤维素钠(33.28g)、166.40g甘露醇和2.96g一水合磷酸二氢钠溶解在纯净水中。总重量为3744g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (33.28 g), 166.40 g of mannitol and 2.96 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 3744g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝386μm；10％直径＝118μm；50％直径＝356μm；90％直径＝1640μm)分散在得到的滤液(1872g)中以形成初级悬浮液。使用Three-One Motor(由HEIDON制造)，由50mm直径叶片以约700至800rpm搅拌来进行制备初级悬浮液的分散工序。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 386 μm; 10% diameter = 118 μm; 50% diameter = 356 μm; 90% diameter = 1640 μm) produced by batch crystallization was dispersed in the obtained filtrate (1872g) to form a primary suspension. The dispersion process for preparing the primary suspension was performed using a Three-One Motor (manufactured by HEIDON) with stirring by a 50 mm diameter blade at about 700 to 800 rpm.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
不进行温度控制，在600bar下通过不连续传送法使获得的二级悬浮液经过高压均质器10次而进行粉碎。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The secondary suspension obtained was comminuted by passing through a high-pressure homogenizer 10 times at 600 bar without temperature control by the discontinuous transfer method. The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表4Table 4
表4表明即使不控制入口温度，可制备平均粒径为约3至5μm的阿立哌唑悬浮液。当控制入口温度时，可获得平均粒径小于3微米的阿立哌唑悬浮液(参见实施例1和2)。Table 4 shows that even without controlling the inlet temperature, aripiprazole suspensions with an average particle size of about 3 to 5 μm can be prepared. When the inlet temperature is controlled, an aripiprazole suspension with an average particle size of less than 3 microns can be obtained (see Examples 1 and 2).
实施例5Example 5
将羧甲基纤维素钠(45.76g)、228.80g甘露醇和4.07g一水合磷酸二氢钠溶解在纯净水中。总重量为5148g。使用粘度为93cps(4％水溶液，25℃)和187cps(4％水溶液，25℃)的羧甲基纤维素钠用于制备。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (45.76 g), 228.80 g of mannitol, and 4.07 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 5148g. Sodium carboxymethylcellulose with a viscosity of 93 cps (4% aqueous solution, 25°C) and 187 cps (4% aqueous solution, 25°C) was used for the preparation. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝239μm；10％直径＝99μm；50％直径＝276μm；90％直径＝632μm)分散在得到的滤液(1872g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 239 μm; 10% diameter = 99 μm; 50% diameter = 276 μm; 90% diameter = 632 μm) produced by batch crystallization was dispersed in the obtained filtrate (1872g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却从而将入口温度保持在约20℃，并在300bar下通过不连续传送法使悬浮液经过高压均质器10次而进行粉碎。The obtained secondary suspension was cooled so as to keep the inlet temperature at about 20° C., and comminuted by passing the suspension through a high pressure homogenizer 10 times at 300 bar by discontinuous transfer.
用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表5table 5
表5表明与实施例3一样，在第二次粉碎步骤中，即使高压均质器的粉碎压力为300bar，CMCNa粘度的差异不影响粉碎作用。Table 5 shows that, as in Example 3, in the second pulverization step, even if the pulverization pressure of the high-pressure homogenizer is 300 bar, the difference in the viscosity of CMCNa does not affect the pulverization.
实施例6Example 6
将羧甲基纤维素钠(183g)、915g甘露醇和16.3g一水合磷酸二氢钠溶解在纯净水中。总重量为20592g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (183 g), 915 g of mannitol and 16.3 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 20592g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(2080g；散装粉末的平均粒径＝246μm；10％直径＝103μm；50％直径＝260μm；90％直径＝548μm)分散在得到的滤液(18720g)中以形成初级悬浮液。Bulk aripiprazole monohydrate produced by batch crystallization (2080 g; average particle size of bulk powder = 246 μm; 10% diameter = 103 μm; 50% diameter = 260 μm; 90% diameter = 548 μm) was dispersed in the obtained filtrate (18720g) to form a primary suspension.
用Clearmix(CLM-9S)以5700rpm、每升2.1分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was comminuted with Clearmix (CLM-9S) at 5700 rpm for 2.1 minutes per liter. As a result, a secondary suspension is obtained.
使获得的二级悬浮液(500ml)经过高压均质器再循环，并在高压均质器的出口处冷却从而将入口温度调节在约15℃至约25℃。在500bar的粉碎压力下将悬浮液粉碎32.5分钟，同时以155mL/min的速率从高压均质器排出。The obtained secondary suspension (500 ml) was recirculated through the high pressure homogenizer and cooled at the outlet of the high pressure homogenizer so as to adjust the inlet temperature at about 15°C to about 25°C. The suspension was pulverized at a pulverization pressure of 500 bar for 32.5 minutes while being discharged from the high pressure homogenizer at a rate of 155 mL/min.
用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎3.25分钟和32.5分钟的悬浮液的平均粒径。结果显示如下。The average particle diameters of the suspensions pulverized for 3.25 minutes and 32.5 minutes were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表6Table 6
表6显示与实施例1-5中所使用的不连续传送法的粉碎一样，再循环法也能够进行所需的粉碎。另外，可见甚至当长时间地通过再循环法反复进行粉碎时，平均粒径不小于1μm。Table 6 shows that the recirculation method was able to achieve the desired comminution as well as the comminution by the discontinuous conveying method used in Examples 1-5. In addition, it was seen that even when the pulverization was repeatedly performed by the recycling method for a long time, the average particle diameter was not smaller than 1 μm.
实施例7Example 7
将羧甲基纤维素钠(45.76g)、228.80g甘露醇和4.07g一水合磷酸二氢钠溶解在纯净水中。总重量为5148g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (45.76 g), 228.80 g of mannitol, and 4.07 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 5148g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝256μm；10％直径＝109μm；50％直径＝272μm；90％直径＝566μm)分散在得到的滤液(1872g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% diameter = 566 μm) produced by batch crystallization was dispersed in the obtained filtrate (1872g) to form a primary suspension.
使用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized using Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液(500ml)冷却从而将入口温度保持在约20℃，并在500bar下经过高压均质器4次而进行粉碎。随后，悬浮液经过高压均质器循环，并在高压均质器的出口处冷却从而将入口温度调节在约20℃。将悬浮液进一步通过再循环法在500bar的粉碎压力下粉碎42分钟，同时以155mL/min的速率排出。The obtained secondary suspension (500 ml) was cooled so as to keep the inlet temperature at about 20° C. and pulverized by passing through a high pressure homogenizer 4 times at 500 bar. Subsequently, the suspension was circulated through a high-pressure homogenizer and cooled at the outlet of the high-pressure homogenizer so as to regulate the inlet temperature at about 20°C. The suspension was further pulverized by a recirculation method at a pulverization pressure of 500 bar for 42 minutes while being discharged at a rate of 155 mL/min.
用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定通过不连续传送法粉碎1次、4次、以及通过不连续传送法粉碎4次并通过再循环法进一步粉碎42分钟的悬浮液的平均粒径。结果显示如下。The particle size distribution analyzer (SALD-3000J, Shimadzu Corp.) was used to measure the particle size of the suspension pulverized 1 time, 4 times by the discontinuous conveying method, and 4 times pulverized by the discontinuous conveying method and further pulverized by the recirculation method for 42 minutes. The average particle size. The results are shown below.
表7Table 7
表7显示不连续传送法可与再循环法组合。此外，即使在长时间反复进行再循环粉碎时，平均粒径也不小于1μm。Table 7 shows that the discontinuous delivery method can be combined with the recirculation method. In addition, even when the recycling pulverization is repeated for a long time, the average particle diameter is not smaller than 1 μm.
实施例8Example 8
将羧甲基纤维素钠(450g)、2250g甘露醇、40g一水合磷酸二氢钠以及160g 1mol/L氢氧化钠水溶液溶解在纯净水中。总重量为50625g。溶液通过0.2μm滤器过滤。将通过分批结晶生产的散装阿立哌唑一水合物(83.2g；散装粉末的平均粒径＝256μm；10％直径＝109μm；50％直径＝272μm；90％直径＝566μm)分散在滤液(748.8g)中以形成初级悬浮液。Sodium carboxymethylcellulose (450g), 2250g mannitol, 40g sodium dihydrogen phosphate monohydrate and 160g 1mol/L sodium hydroxide aqueous solution were dissolved in purified water. The total weight is 50625g. The solution was filtered through a 0.2 μm filter. Bulk aripiprazole monohydrate (83.2 g; average particle size of bulk powder = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% diameter = 566 μm), produced by batch crystallization, was dispersed in the filtrate ( 748.8 g) to form a primary suspension.
用将剪切力施加于待加工德材料的分散机(商品名：“T-50Basic”，由IKA Japan，Inc.制造)，采用通用名称为轴传动发电机(shaft generator)的轴(商品名：“S50N-G45G”，由IKA Japan，Inc.制造)以6400rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。With a dispersing machine (trade name: "T-50Basic", manufactured by IKA Japan, Inc.) that applies shear force to the material to be processed, a shaft (trade name: : "S50N-G45G", manufactured by IKA Japan, Inc.) pulverized the primary suspension at 6400 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却从而将入口温度保持在约20℃，并通过不连续传送法在300bar下经过高压均质器1次且在500bar下经过高压均质器四次而总共粉碎5次。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎1次和粉碎5次的悬浮液的平均粒径。结果显示如下。The obtained secondary suspension was cooled so as to keep the inlet temperature at about 20° C. and comminuted by the discontinuous transfer method through the high pressure homogenizer once at 300 bar and four times at 500 bar for a total of 5 times . The average particle diameters of the suspensions pulverized 1 time and pulverized 5 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表8Table 8
表8表明对于第一次粉碎可使用任何粉碎机，只要它们具有一定程度的剪切力以粉碎散装粉末。不仅可使用前述的高剪切高速搅拌机(例如，Clearmix)，而且还可使用分散机(例如，由IKA Japan，Inc.制造的“T-50Basic”)。Table 8 shows that any pulverizer can be used for the first pulverization as long as they have a certain degree of shear to pulverize the bulk powder. Not only the aforementioned high-shear high-speed mixer (for example, Clearmix) but also a disperser (for example, "T-50Basic" manufactured by IKA Japan, Inc.) can be used.
实施例9Example 9
将羧甲基纤维素钠(450g)、2250g甘露醇、40g一水合磷酸二氢钠以及160g 1mol/L氢氧化钠水溶液溶解在纯净水中。总重量为50625g。溶液通过0.2μm滤器过滤。将通过分批结晶生产的散装阿立哌唑一水合物(83.2g；散装粉末的平均粒径＝256μm；10％直径＝109μm；50％直径＝272μm；90％直径＝566μm)分散在滤液(748.8g)中以形成初级悬浮液。Sodium carboxymethylcellulose (450g), 2250g mannitol, 40g sodium dihydrogen phosphate monohydrate and 160g 1mol/L sodium hydroxide aqueous solution were dissolved in purified water. The total weight is 50625g. The solution was filtered through a 0.2 μm filter. Bulk aripiprazole monohydrate (83.2 g; average particle size of bulk powder = 256 μm; 10% diameter = 109 μm; 50% diameter = 272 μm; 90% diameter = 566 μm), produced by batch crystallization, was dispersed in the filtrate ( 748.8 g) to form a primary suspension.
将初级悬浮液冷却从而将入口温度保持在约20℃，并通过不连续传送法在100bar下经过高压均质器1次(第一次粉碎步骤)，以及在300bar下经过高压均质器一次且在500bar下经过高压均质器四次(第二次粉碎步骤)而总共粉碎6次。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎1次、粉碎2次和粉碎6次的悬浮液的平均粒径。结果显示如下。The primary suspension was cooled so as to keep the inlet temperature at about 20 °C and passed through the high pressure homogenizer once at 100 bar (first pulverization step) and once at 300 bar by discontinuous transfer method and Four passes through the high pressure homogenizer at 500 bar (second comminution step) for a total of 6 comminutions. The average particle diameters of the suspensions pulverized 1 time, pulverized 2 times and pulverized 6 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表9Table 9
表9显示如果使用较低的粉碎压力，即使高压均质器也可用于第一次粉碎步骤而不会在管线中导致堵塞。Table 9 shows that even a high pressure homogenizer can be used for the first crushing step without causing plugging in the lines if lower crushing pressures are used.
实施例10Example 10
将羧甲基纤维素钠(16.64g)、83.20g甘露醇和1.48g一水合磷酸二氢钠溶解在纯净水中。总重量为3704g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (16.64 g), 83.20 g of mannitol and 1.48 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 3704g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝238μm；10％直径＝72μm；50％直径＝274μm；90％直径＝811μm)分散在得到的滤液(1852g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 238 μm; 10% diameter = 72 μm; 50% diameter = 274 μm; 90% diameter = 811 μm) produced by batch crystallization was dispersed in the obtained filtrate (1852g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
不进行温度控制，通过不连续传送法使获得的二级悬浮液在600bar下经过高压均质器10次而进行粉碎。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The obtained secondary suspension was comminuted by passing through a high pressure homogenizer 10 times at 600 bar without temperature control. The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表10Table 10
表10表明即使不控制入口温度，也可制备平均粒径为约3至5μm的阿立哌唑悬浮液。当控制入口温度时，可获得平均粒径小于3微米的阿立哌唑悬浮液(参见下面的实施例11)。Table 10 shows that even without controlling the inlet temperature, aripiprazole suspensions with a mean particle size of about 3 to 5 μm can be prepared. When the inlet temperature is controlled, an aripiprazole suspension with an average particle size of less than 3 microns can be obtained (see Example 11 below).
实施例11Example 11
将羧甲基纤维素钠(16.64g)、83.20g甘露醇和1.48g一水合磷酸二氢钠溶解在纯净水中。总重量为3704g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (16.64 g), 83.20 g of mannitol and 1.48 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 3704g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝238μm；10％直径＝72μm；50％直径＝274μm；90％直径＝811μm)分散在得到的滤液(1852g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 238 μm; 10% diameter = 72 μm; 50% diameter = 274 μm; 90% diameter = 811 μm) produced by batch crystallization was dispersed in the obtained filtrate (1852g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却从而将入口温度保持在约20℃，并通过不连续传送法使悬浮液在600bar下经过高压均质器10次而进行粉碎。The obtained secondary suspension was cooled so as to keep the inlet temperature at about 20° C., and comminuted by passing the suspension through a high pressure homogenizer at 600 bar 10 times by the discontinuous transfer method.
用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表11Table 11
表11表明即使当作为悬浮剂的CMCNa的浓度很低时，第一次传送能制备具有1至5μm的平均粒径的悬浮液，传送10次能制备具有2μm的平均粒径的悬浮液。Table 11 shows that even when the concentration of CMCNa as a suspending agent is low, the first pass can prepare a suspension with an average particle diameter of 1 to 5 μm, and 10 passes can prepare a suspension with an average particle diameter of 2 μm.
实施例12Example 12
将羧甲基纤维素钠(16.64g)、83.20g甘露醇和1.48g一水合磷酸二氢钠溶解在纯净水中。总重量为3704g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (16.64 g), 83.20 g of mannitol and 1.48 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 3704g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(208g；散装粉末的平均粒径＝258μm；10％直径＝99μm；50％直径＝280μm；90％直径＝609μm)分散在得到的滤液(1852g)中以形成初级悬浮液。Bulk aripiprazole monohydrate (208 g; average particle size of bulk powder = 258 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm) produced by batch crystallization was dispersed in the obtained filtrate (1852g) to form a primary suspension.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液冷却或加温从而将入口温度保持在约10℃、约20℃、约40℃和约60℃，并通过不连续传送法使悬浮液在600bar下经过高压均质器10次而进行粉碎。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎一次和粉碎10次的悬浮液的平均粒径。结果显示如下。The secondary suspension obtained is cooled or warmed so as to maintain the inlet temperature at about 10°C, about 20°C, about 40°C and about 60°C, and the suspension is passed through a high pressure homogenizer 10 at 600 bar by discontinuous transfer method Then crush it. The average particle diameters of the suspensions pulverized once and pulverized 10 times were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表12Table 12
表12表明：Table 12 shows that:
(i)即使当CMCNa浓度很低时，可如实施例1一样制备平均粒径为1至5μm的悬浮液。(i) Even when the concentration of CMCNa is very low, a suspension having an average particle diameter of 1 to 5 µm can be prepared as in Example 1.
(ii)即使当CMCNa浓度很低时，可如实施例1一样通过将入口温度调节至40℃或更低而制备平均粒径为2至3μm的悬浮液。(ii) Even when the concentration of CMCNa is low, a suspension having an average particle diameter of 2 to 3 μm can be prepared as in Example 1 by adjusting the inlet temperature to 40° C. or lower.
实施例13Example 13
将羧甲基纤维素钠(8.32g)、41.60g甘露醇和0.74g一水合磷酸二氢钠溶解在纯净水中。总重量为1852g。用1mol/L氢氧化钠水溶液将溶液调节至pH 7.0，并通过0.2μm滤器过滤。Sodium carboxymethylcellulose (8.32 g), 41.60 g of mannitol and 0.74 g of sodium dihydrogen phosphate monohydrate were dissolved in purified water. The total weight is 1852g. The solution was adjusted to pH 7.0 with 1 mol/L aqueous sodium hydroxide solution and filtered through a 0.2 μm filter.
将通过分批结晶生产的散装阿立哌唑一水合物(83.2g；散装粉末的平均粒径＝256μm；10％直径＝99μm；50％直径＝280μm；90％直径＝609μm)分散在得到的滤液(740.8g)中以形成初级悬浮液。通过使用Three One Motor(由HEIDON制造)，采用50mm直径叶片以约300至500rpm搅拌来进行制备初级悬浮液的分散程序。Bulk aripiprazole monohydrate (83.2 g; average particle size of bulk powder = 256 μm; 10% diameter = 99 μm; 50% diameter = 280 μm; 90% diameter = 609 μm) produced by batch crystallization was dispersed in the obtained filtrate (740.8 g) to form a primary suspension. The dispersion procedure for preparing the primary suspension was carried out by using a Three One Motor (manufactured by HEIDON) with a 50 mm diameter blade stirring at about 300 to 500 rpm.
用Clearmix(CLM-1.5S)以18000rpm、每升7.5分钟，对初级悬浮液进行粉碎。结果，获得二级悬浮液。The primary suspension was pulverized with Clearmix (CLM-1.5S) at 18000 rpm for 7.5 minutes per liter. As a result, a secondary suspension is obtained.
将获得的二级悬浮液(450ml)通过高压均质器循环，并在高压均质器的出口处冷却从而将入口温度调节至约20℃。The obtained secondary suspension (450 ml) was circulated through the high pressure homogenizer and cooled at the outlet of the high pressure homogenizer so as to adjust the inlet temperature to about 20°C.
悬浮液在500bar的粉碎压力下通过再循环法粉碎72.5分钟，同时以155mL/min的速率从高压均质器排出。用粒径分布分析仪(SALD-3000J，Shimadzu Corp.)测定粉碎14.5分钟和粉碎72.5分钟的悬浮液的平均粒径。结果显示如下。The suspension was pulverized by a recirculation method at a pulverization pressure of 500 bar for 72.5 minutes while being discharged from the high pressure homogenizer at a rate of 155 mL/min. The average particle diameters of the suspensions pulverized for 14.5 minutes and pulverized for 72.5 minutes were measured with a particle size distribution analyzer (SALD-3000J, Shimadzu Corp.). The results are shown below.
表13Table 13
表13显示即使CMCNa浓度很低，也能够通过再循环法进行所需的粉碎；另外，即使当长时间地反复进行再循环粉碎时，平均粒径也不小于1μm。Table 13 shows that even when the concentration of CMCNa is low, desired pulverization can be performed by the recycling method; also, even when the recycling pulverization is repeated for a long time, the average particle diameter is not less than 1 μm.
实施例14Example 14
将通过实施例1-13中所示的方法获得的各阿立哌唑悬浮液(2.5mL)倒入玻璃瓶中，并用橡胶瓶塞部分地将瓶子塞住。将瓶子转移至冷冻干燥机并在下列条件下冻干：Each aripiprazole suspension (2.5 mL) obtained by the method shown in Examples 1-13 was poured into a glass bottle, and the bottle was partially stoppered with a rubber stopper. Transfer the vials to a freeze dryer and lyophilize under the following conditions:
(a)冷冻：将瓶子以1℃/min冷却至-40℃，然后在-40℃下保持6小时；(a) Freezing: Cool the bottle to -40°C at 1°C/min, then keep at -40°C for 6 hours;
(b)干燥：室压降低至约13Pa，且冷冻干燥机的搁板(shelf)温度以0.3℃/min的速率增加至-5℃；然后持续干燥55.5小时，同时真空度保持在约13Pa，且搁板温度保持在约-5℃；(b) drying: the chamber pressure was reduced to about 13Pa, and the shelf temperature of the freeze dryer was increased to -5°C at a rate of 0.3°C/min; then the drying was continued for 55.5 hours while the vacuum was maintained at about 13Pa, And the shelf temperature is kept at about -5°C;
(c)在使用氮气或空气的大气压或部分真空下将瓶子塞住，然后从冷冻干燥机中移出；并且(c) stopper the vial under atmospheric pressure or partial vacuum using nitrogen or air and remove from the freeze dryer; and
(d)用铝封将瓶子密封。(d) The bottle is sealed with an aluminum seal.
得到的各冻干阿立哌唑悬浮液的阿立哌唑为水合物A。The aripiprazole in each obtained freeze-dried aripiprazole suspension was Hydrate A.
实施例15Example 15
将通过实施例1-13中所示的方法获得的各阿立哌唑悬浮液倒入玻璃瓶中，并用橡胶瓶塞部分地将瓶子塞住。将瓶子转移至冷冻干燥机并在下列条件下冻干：Each of the aripiprazole suspensions obtained by the methods shown in Examples 1-13 was poured into glass bottles, and the bottles were partially stoppered with rubber stoppers. Transfer the vials to a freeze dryer and lyophilize under the following conditions:
(a)冷冻：将瓶子以1℃/min冷却至-40℃，然后在-40℃下保持6小时；(a) Freezing: Cool the bottle to -40°C at 1°C/min, then keep at -40°C for 6 hours;
(b)初步干燥：室压降低至约13Pa，且冷冻干燥机的搁板温度以0.3℃/min的速率增加至-5℃；然后持续初步干燥55.5小时，同时真空度保持在约13Pa，且搁板温度保持在约-5℃；(b) Preliminary drying: the chamber pressure is reduced to about 13Pa, and the shelf temperature of the freeze dryer is increased to -5°C at a rate of 0.3°C/min; then the preliminary drying is continued for 55.5 hours while the vacuum is maintained at about 13Pa, and The shelf temperature is maintained at about -5°C;
(c)第二次干燥：隔板温度增加至25℃，并持续干燥24小时，同时真空度保持在约13Pa；然后将搁板温度增加至50℃，并持续干燥24小时，同时真空度保持在约13Pa；(c) The second drying: increase the shelf temperature to 25°C and continue drying for 24 hours while keeping the vacuum at about 13Pa; then increase the shelf temperature to 50°C and continue drying for 24 hours while maintaining the vacuum at about 13Pa;
(d)在使用氮气或空气的大气压或部分真空下将瓶子塞住，然后从冷冻干燥机中移出；并且(d) stopper the vial under atmospheric pressure or partial vacuum using nitrogen or air and remove from the freeze dryer; and
(e)用铝封将瓶子密封。(e) The bottle is sealed with an aluminum seal.
得到的各冻干阿立哌唑悬浮液的阿立哌唑为无水形式。The aripiprazole of each lyophilized aripiprazole suspension was obtained in anhydrous form.
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| CN103025318A (en)* | 2010-08-24 | 2013-04-03 | 大塚制药株式会社 | Suspension and cake composition containing carbostyryl derivative and silicone oil and/or silicone oil derivative |
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| TWI594753B (en)* | 2011-01-24 | 2017-08-11 | 大塚製藥股份有限公司 | A medical device comprising a block composition comprising aripiprazole as an active ingredient, and a block composition comprising aripiprazole as an active ingredient |
| CN103596557A (en)* | 2011-06-07 | 2014-02-19 | 大塚制药株式会社 | Freeze-dried formulation of aripiprazole |
| CN102524261A (en)* | 2011-12-16 | 2012-07-04 | 辽宁师范大学 | Nanometer preparation of strong rooting agent, preparation method and application thereof |
| CN102524261B (en)* | 2011-12-16 | 2014-12-03 | 辽宁师范大学 | Nanometer preparation of strong rooting agent, preparation method and application thereof |
| CN102450269A (en)* | 2011-12-27 | 2012-05-16 | 辽宁师范大学 | Triazolone nano colloidal suspension and preparation method thereof |
| CN104470499B (en)* | 2012-04-23 | 2018-03-16 | 大塚制药株式会社 | injectable formulation |
| CN107536802A (en)* | 2012-04-23 | 2018-01-05 | 大塚制药株式会社 | Injection |
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| US10624889B2 (en) | 2012-04-23 | 2020-04-21 | Otsuka Pharmaceutical Co., Ltd. | Injectable formulation |
| US11786522B2 (en) | 2015-08-31 | 2023-10-17 | Nanjing Noratech Pharmaceuticals Co., Ltd | Aripiprazole injectable suspension formulation having prolonged shelf life |
| CN106474058A (en)* | 2015-08-31 | 2017-03-08 | 诺瑞特国际药业股份有限公司 | Injectable aripiprazole suspension formulations with extended shelf life |
| WO2017036118A1 (en)* | 2015-08-31 | 2017-03-09 | 诺瑞特国际药业股份有限公司 | Injectable aripiprazole suspension preparation having prolonged shelf life |
| CN106474058B (en)* | 2015-08-31 | 2020-01-07 | 南京诺瑞特医药科技有限公司 | Aripiprazole injectable suspension formulation with extended shelf life |
| US12433887B2 (en) | 2015-08-31 | 2025-10-07 | Nanjing Noratech Pharmaceuticals Co., Ltd | Aripiprazole injectable suspension formulation having prolonged shelf life |
| CN108938578A (en)* | 2017-05-25 | 2018-12-07 | 万全万特制药（厦门）有限公司 | Aripiprazole dispersible tablet and preparation method thereof |
| CN115554253B (en)* | 2022-10-14 | 2024-03-29 | 浙江圣兆药物科技股份有限公司 | Aripiprazole freeze-dried preparation for injection capable of stably releasing medicine and preparation method thereof |
| CN115554253A (en)* | 2022-10-14 | 2023-01-03 | 浙江圣兆药物科技股份有限公司 | Aripiprazole freeze-dried preparation for injection with stable drug release and preparation method thereof |
| CN117281784A (en)* | 2023-11-24 | 2023-12-26 | 山东则正医药技术有限公司 | Aripiprazole injection and preparation method and application thereof |
| CN117281784B (en)* | 2023-11-24 | 2024-02-27 | 山东则正医药技术有限公司 | Aripiprazole injection and preparation method and application thereof |
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